Biochemistry Flashcards

(556 cards)

1
Q

What is a cell?

A

Basic structural, functional and biological unit of all living organisms
Smallest unit of life replicate indecently
Require nutrients and produce waste

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2
Q

Describe the cell membrane

A

Selectively permeable biological membrane separating interior and exterior of cell and protecting from surroundings
Involved in cell adhesion, ion conductivity, cell signalling, attachment surface for cell wall, glycocalyx (glycoprotein-polysaccharide surrounding CM of some bacteria and epithelial) and intracellular cytoskeleton

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3
Q

Describe the phospholipid bilayer

A

Made of hydrophilic heads and hydrophobic tails
Phospholipids spontaneously form self-sealing bilayers
Due to hydrophobic interior charged ions cannot diffuse
Fluid - components move around easily
Mosaic - variety of lipids and proteins

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4
Q

Describe centrosomes

A
Associated with nuclear membrane in prophase
In mitosis, NM breaks down and centrosome nucleated microtubules (cytoskeleton) interact with chromosomes to build mitotic spindle
Mother centrosome (oldest) role in making cilia and flagella
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5
Q

Describe lysosomes

A

Membrane bound organelle that functions as recycling centre by digesting unwanted material in cytoplasm from extracellular and obsolete intracellular components
Contains hydrolytic enzymes capable of digesting almost all biomolecules: proteins, nucleic acids, carbs, lipids, debris
50+ enzymes all active at about pH 5

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6
Q

Describe the cytosol/ICF

A

Liquid found inside cells separated into compartments by membranes i.e. mitochondrial matrix separates cells into compartments
Eukaryotes - ICF in CM and part of cytoplasm (mitochondria, plastids, organelles minus internal fluids and nucleus

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7
Q

Describe the vacuole

A

Membrane bound organelle filled with water containing in/organic molecules (enzymes in solution), sometimes engulfed solids
Formed by fusion of multiple vesicles
Shape and function varies depending on needs and type of cell
Role in autophagy, balance between biogenesis and degradation, lysis and recycling of mis-folded proteins

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8
Q

Describe mitochondria

A

Membrane bound organelles
Main functions are to produce ATP in TCA (respiration) and regulate metabolism
Role in - signalling through mitochondrial reactive O2 specifies
Regulate - MP, apoptosis, Ca signalling (including Ca-apoptosis), cellular metabolism, heme and steroid synthesis
Have oestrogen receptors (mtERs) thus sensitive to hormones
In liver cells, have enzymes that detoxify ammonia (waste product of protein metabolism)

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9
Q

Describe the smooth ER

A

Site of lipid, phospholipid and steroid synthesis connected to nuclear envelope
Abundant in cells (ovaries, testes, skin oil glands) that secrete these products
Metabolism of carbs and steroids, drug detoxification, attachments of receptors on CMPs
Muscle cell - regulates Ca ion conc.

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10
Q

Describe the cytoskeleton

A

Dynamic structure made of microfilaments (actin), microtubules (tubulin) and intermediate filaments (only found in animal cells) forming framework for movement of organelles and cell shape

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11
Q

Describe the Golgi body

A

Modifies, sorts and packages macromolecules for exocytosis or use with in cell primarily those delivered by RER
Transports lipids and involved in creation of lysosomes
N/O-linked goycosylation

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12
Q

Describe the rough ER

A

Complex responsible for manufacture of lysosomal enzymes (mannose-6-phosphate marker added in cis-Golgi network)
Manufacture of secreted proteins secreted either constitutively (no tag) or regulatory (clathrin and basic AA in signal peptide)
Initial stage of N-linked glycosylation

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13
Q

Describe a vesicle

A

Variety of functions
Internal environment different from cytosolic as is separate from cytosol thus used for organising cellular substances
Involved in metabolism, transport, buoyancy control, enzyme storage (ready for immediate release), chemical reaction chambers

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14
Q

Describe ribosomes

A

Site of gene translation
Attaches to mRNA, reads codon. tRNA with complementary anti-codon recruited bringing specific AA building protein.
Continues until reaches stop codon, if none will remain attached forming complex

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15
Q

Describe the nucleus

A

Cell control centre: maintains integrity of genes and regulates gene expression
Contains DNA and histone proteins to form chromosomes
Has double membrane enclosing entire organelle isolating from cytoplasm, nuclear envelopes and nucleoskeleton (like cytoskeleton)

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16
Q

Describe nucleolus

A

Organelle found in nucleus that forms around specific chromosomal a previous in nucleus
Made of proteins and RNA
Transcribe and modify rRNA and integrate ribosomal proteins into immature ribosomes
Stress sensor and able to regulate rRNA synthesis based on cell environment

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17
Q

Describe the differences between prokaryotes and eukaryotes

A

Lack membrane bound nucleus (have nucleoid) and complex organelles
Ribosomal binding site in mRNA is the Shine Delgarno sequence: 8 bases up from AUG
Have mesosomes - folds inwards in PM that increase SA, can be artefact (damage to PM during chemical fixation)
Have cell wall, capsules and flagella (chemotaxis - movement of organism in response to chemical stimuli

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18
Q

Describe gram +ve bacteria (purple)

A

Thick cell wall of peptidoglycan which is mesh that gives strength
Cell would be spherical and v sensitive to osmotic changes without

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19
Q

Describe gram -ve bacteria (red)

A

Complex cell wall external to PM with thin peptidoglycan layer
Have outer membrane with lipopolysaccharides conferring
Structural integrity, resistance to chem. attack, toxicity (septic shock, death)

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20
Q

How do many antibiotics work?

A

Act by inhibiting cell wall synthesis

B-lactam antibiotics (Penicillins) interfere with peptidoglycan synthesis causing cell lysis

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21
Q

What is pH?

A

Logarithmic measure of conc. of H+ ions (protons) in solution
pH = -log[H+]

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22
Q

What is the physiological pH of the body and why is this important?

A

pH 7.4
pH affects solubility of substances and the activity of biological systems thus keeping pH constant is important for body
Blood pH<7.3 acidosis
Blood pH>7.5 alkalosis

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23
Q

Define acid, base, conjugated acid and conjugated base

A

Acid - proton donator, gains -ve charge
Base - proton acceptor, gains +ve charge
Conjugated acid - species formed from addition of H+
Conjugated base - what is left after acid donates proton

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24
Q

What is the major respiratory acid in the body and how is it formed?

A

CO2
Dissolved in water forming carbonic acid which dissociates releasing H+
CO2 + H2O H2CO3 H+ + HCO3-

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25
Name some metabolic acids and how they produced
Organic (lactic, uric) and inorganic (sulphuric) produced by metabolism of AAs containing phosphorus and sulphur Lactic - product of anaerobic glycolysis Keto acids - ketoacidosis, lack of insulin Drugs - aspirin
26
Define buffer
Solution that resists changes in pH when acid/alkali is added to it Usually a solution of weak acid and its conjugate base Biological fluids have ENDOGENOUS buffers
27
How do buffers work?
Weak acid will partially dissociate and salt will fully dissociate allowing H+/OH- ions to be added and equilibrium will shift to replace the lost molecules As one fully dissociates more ions will be produced and not removed
28
What are the main buffers in the body and where are they found?
Haemoglobin (HHb) found in red blood cells Proteins (HProt) in intracellular fluid Phosphate (H2PO4-) in intracellular fluid BICARBONATE (CO2->H2CO3) - blood plasma, interstitial fluid
29
Define buffer capacity
Extent of resistance to pH change i.e. how much acid/base added before pH changes dramatically
30
What is the dissociation constant?
Kd - Type of equilibrium constant that measures the dissociation of larger compound to split reversible to smaller components
31
What is pK(a)?
The pH at which 50% of the HA (acid) has ionised
32
What is the Henderson-Hasselbalch equation?
pH = pK + log[A-]/[HA]
33
What is the relationship between pH, pKa and ionisation?
If the pKa is higher than pH, acid is less likely to be ionised
34
What is critical pH?
pH at which tooth becomes unsaturated with respect to Ca and PO43- allowing hydroxyapatite in enamel to dissolve Region of pH 5.2-5.5
35
How does saliva protect teeth from decay?
Produces many buffers (principally bicarbonate) which prevent resting pH falling much lower than pH 6.3
36
What are the main buffers in saliva and how effective are they?
Proteins - not effective as nearly all charged groups from peptide bonds Phosphate - good but not in high enough conc. to be effective Bicarbonate - good
37
What is the role of bicarbonate in plaque?
Acts to neutralise acid rather than buffer acid | Produces H+ pushing reaction to right producing CO2 and H2O - CO2 released as mouth open system
38
What conc. does carbonic acid stay at in the mouth and what changes?
About 1.3mMol/L | pH and [HCO3-] change, bicarbonate varies with flow rate
39
What must all AAs have?
Amino (NH2), carboxyl (COOH), H and R group | a-carbon is C atom amino and carboxyl groups are attached
40
What is the role of side chains?
Are the functional groups Determine structure, function and charge of AAs Charged, polar or hydrophilic R groups exposed on surface Non-polar, hydrophobic R groups buried in interior
41
What confers an AAs' optical activity?
An asymmetric C atom - C attached to 4 different groups | All AAs except GLYCINE (R group = H) are asymmetric
42
What does being asymmetric mean?
Means compound has spatially distinct but chemically identical isomers that are mirror images of each other (enamtiomers) Both are optically active (rotate plane polarised light) to right (Dextro) or to left (Levo - majority of AAs)
43
What is a zwitterion?
A molecule that bears groups of opposite polarity | As amino and carboxylic acid groups readily ionise AAs are dipolar/zwitterions
44
How does the charge of AAs change with increasing pH?
Low pH - amino protonated, carboxyl normal pH 7 - amino protonated, carboxyl ionised High pH - amino normal, carboxyl ionised
45
Define AMPHOTERIC
Molecules that have both acidic and basic groups | AAs are amphoteric
46
Define anion
A negative ions from gain of e-
47
Define cations
+ve charged molecule
48
Name the aliphatic AAs? (Hydrophobic/non-polar) | VIGAL
``` V - valine I - isoleucine G - glycine A - alanine L - leucine ```
49
Name the aromatic AAs | Y+T
Phenylalanine (phenol - aromatic) Tryptophan (Y + T = aromatic) Both non-polar Tyrosine (Y + T)
50
Name the sulphur containing AAs | MC Sulphur
M - methionine C - cysteine (can from S-S, stabilise proteins) MC Sulphure
51
Name the neutral polar AAs
Hydroxy-Soft Towel Serine Threonine Amide derivates of Acids Asparagine Glutamine
52
What is the ImIno acid?
Proline - causes bends in polypeptides
53
Name acidic AAs
Aspartic acid Glutamic acid COOH R group - ionised at pH 7
54
Name the basic AAs | Larry is basic
L - lysine Ar - arginine His - histidine LArHis - extra +ve charge
55
What formula is used to calculate the isoelectric point? How is this calculated for amino acids with 2 carboxyl/amino groups?
pI = (pKa + pKb)/2 a (acidic) = COOH b (basic) = NH2 For 2 carboxyl groups the (pKa1 + pKa2)/2 is used
56
What is a dalton?
Da is a unit of molecular weight equivalent to 1 H atom | Compares how heavy something is to H
57
Describe the primary structure of a protein
Unique sequence of AAs held by peptide bonds | Compare structure to find common sequences suggesting members of a multigene family
58
Describe the secondary structure of proteins
H bonding determines secondary structure either a-helix or B-pleated sheet
59
Describe boding in and structure of an a-helix
N atom in peptide bond shares H atom with CO group 4 residues upstream Polypeptide twists around in a spiral, each turn takes 3.6 AAs residues
60
Describe B-pleated sheets
B strands laterally connected by 2/3 H bonds | Typically 3-10 AAs long
61
Describe the tertiary structure of AAs
Folding of secondary requiring series of non-covalent interactions Held by electrostatic, VDWs, disulphide, hydrophobic interactions
62
What are electrostatic bonds?
Strong interactions between ions/charged groups of opposite charge In protein called a salt bridge
63
What are Van der Waals forces?
Weak, close range temporary dipole-dipole interactions
64
What are disulphide bonds?
Strong covalent S-S bonds between specific cysteine residues Tend to lock molecule into configuration allowing it to withstand v high temperatures
65
What are hydrophobic interactions?
Interactions between polar and non-polar molecules causing the spontaneous folding of hydrophobic residues away from water
66
Describe the quaternary structure of proteins
Association of multiple tertiary polypeptides | Haemoglobin is association of 4 globin groups and 4 heme groups
67
What is a protein domain?
Part of a polypeptide that can fold independently of polypeptide into compact, stable tertiary structure Usually identified by presence of prolIne Can be cut, isolated and studied separately from main chain
68
What is protein folding?
Process by which higher structures are formed from primary (AA) sequence
69
What are transitions in shape of tertiary or quaternary structures called?
Conformational changes - proteins may shift between several similar structures in performing their function (Tertiary and quaternary structures referred to as conformations)
70
What is the reversible nature of protein folding dependent on?
Primary structure being maintained
71
What are the three classes of proteins?
Fibrous Globular Membrane-associated
72
Describe globular proteins
Are soluble, nearly all enzymes are globular | Carbonic anhydrase and haemoglobin are examples
73
Describe carbonic anhydrase
Catalyses interconversion of CO2 + H2O to carbonic acid Different classes have little sequential or structural similarities but share identical AS thus all perform same function and require a Zn atom Contains large B sheet in centre
74
Describe haemoglobin
Assembly of 4 globular protein subunits each composed of protein chain (2 a chains, 2 B chains) tightly associated with prosthetic heme group
75
What is a prosthetic group?
Non-protein group tightly bound to protein that confers function Heme has an Fe atom held in heterocyclic ring equally to all 4 N atoms Fe is site of O2 binding
76
Describe fibrous proteins
Form rod/wire like shapes, usually structural or storage proteins AA sequence often lacks repeating units From unusual 2ndary structures (collagen triple helix) due to cross-links between chains e.g. S-S bonds between keratin Usually used to construct CT, tendons, bone matrix, muscle fibre
77
What are keratins and what do they form?
Family of fibrous structural proteins, they are tough and insoluble Form non-mineralised structures found in reptiles, birds, amphibians, mammals (hair)
78
Describe the structure of keratin
High proportion of glycine (smallest) and alanine (2nd smallest) AAs High amounts of cysteine (sulphur containing) required for S-S bridges confer strength, rigidity by permanent, thermally stable cross-links
79
Describe the structure of keratin monomer and the assembly into intermediate filaments
3 domains: head, rod, tail | Monomers associate to dimers, associate to tetramers, finally to intermediate filaments forming part of cytoskeleton
80
What is collagen?
Family of fibrous proteins secreted by CTs with triple helix AA structure 28 different types Unique sequence of glycine-proline/hydroxyproline-alternative AA
81
What are the 3 type of membrane-associated proteins?
``` Transmembrane (intrinsic) - cross membrane, usually a-helix Lipid associated (extrinsic) - bound to outer surface Proteins attached to transmembrane protein - increase ionic strength to detach i.e. add NaCl ```
82
What are the 2 domains of membrane proteins?
Interdomain - intracellular | Outer domain - extracellular
83
What are some of the functions of membrane proteins?
Transporters, linkers, receptors, enzymes
84
Define enzyme
Proteins that catalyse biochemical reactions (biological catalysts)
85
Define active site
Parts of enzyme that react with substrate (+ cofactors) in reaction
86
Define co-enzyme
Small, diffusible organic residue that participates in enzyme catalysed reaction, is stable to heat
87
Define prosthetic group
Coenzyme covalently bound to enzyme so that not removed by dialysis
88
Define zymogen
Inactive precursor of enzyme
89
Define holoenzyme
Protein (apoenzyme) with coenzyme/ions required for activity
90
Define apoenzyme
Protein with coenzyme required for activity, liable to heat
91
Define substrate
Molecule on which enzyme performs a reaction
92
What is lysozyme?
An enzyme found in tissue fluids/secretions, tears, saliva, nasal mucus that protects against bacteria by causing cell to lyse and lose cell content
93
What is peptidoglycan?
Polysaccharide formed from polymerisation of monosaccharides N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM)
94
Describe the structure of bacterial cell wall
Made of peptidoglycan - retains high internal osmotic pressure Layers of repeating peptidoglycan units with peptide chain bound to NAM Penta-glycine cross-links between last residue of chain and second last of opposite chain - added strength
95
Describe alpha and beta linkages
Alpha: H atoms of the C atoms in bond in cis formation Beta: H atoms of C atoms in bond in trans formation
96
Describe the lysis of the cell wall
Lysozyme hydrolyses B1:4 bond (between C1 and C4) in glycan between NAG and NAM Occurs rapidly at close to pH 7
97
What else will lysozyme hydrolyse?
``` Oligo NAG (min 6 residues) Fit into groove round enzyme that closes on the strand ```
98
What are serine proteases?
Enzymes with hyperactive serine residue at active site and appropriately spaced histidine and aspartate resides
99
Name some serine proteases
Trypsin Chymotrypsin Elastase Thrombin
100
How do serine proteases work?
Catalyse by breaking peptide bond using charge relay system
101
Describe the charge relay system
Flow of electrons between 3 AAs making serine hyperactive | AAs are far apart in primary structure but close in 3D structure due to protein folding
102
Why are proteolytic enzymes secreted as zymogens?
As are hazardous to body so secreted as zymogens that are activated in gut lumen
103
Give examples of proteolytic enzymes
Pepsinogen Tryspinogen Chymotrypsinogen
104
Describe the activation of pepsinogen
Chief cells in gastric gland produce pepsinogen Parietal cells produce HCl hydrolyses some peptide bonds to produce pepsin Left over pepsinogen is hydrolysed again to produce more pepsin
105
Describe the activation of trypsinogen
Pancreatic duct secretes pancreatic zymogens Some zymogens converted to trypsinogen which is converted to trypsin by enterokinase (produced by brush border) Trypsin activates more enzymes such as chymotrypsinogen
106
Describe the activation of chymotrypsinogen
Inactive state: single polypeptide, 245AAs with 5 SS bridges, three portions of AS caN'T come together Trypsin cuts bond between Arg15 and next residue - pi-chymotrypsin left Cut at Leu13 removes dipeptide bond Cut at Tyr146 and Asn148 removes another - a-chymotrypsin 3 parts held by SS bridges Active site resides come together Charge transfer complex with hyperactive serine formed
107
How is specificity of enzymes dictated?
Pocket close to AS into which an AA side chain may fit thus size and nature of pocket are important
108
Describe the specificity of trypsin, chymotrypsin and elastase
Trypsin: cuts basic R groups; Asp at bottom of pocket Chymotrypsin: cuts hydrophobic R; hydrophobic pocket Elastase: cuts small R; small pocket
109
Describe the steady state hypothesis
In enzyme catalysed reaction, enzyme and substrate form complex which is a transient state (either breaking down or reversing) Initially conc. of complex will increase but will become steady as when broken down enzyme will form new complex
110
What is Vmax?
The velocity a reaction approaches as substrate conc. is increased
111
What is Michaelis constant (Km)?
Substrate conc. at 1/2Vmax Dependent on substrate and enzyme Measures affinity of enzyme for substrate - a high Km confers low affinity
112
What is the relationship between substrate conc. and velocity?
Michaelis-Menten equation v = Vmax[S]/(Km+[S]) When [s]=Km v = 1/2Vmax When [s]>>Km v ~ Vmax
113
What is the importance of Km?
Can use to compare 1 enzyme's affinity for different substrates or Multiple enzymes affinities' for 1 substrate
114
Describe hexokinase
Phosphorylates glucose Widespread in tissue Low Km = high affinity Always active
115
Describe glucokinase
Found in liver and pancreas High Km = low affinity only active at high glucose conc. At high conc. glucose stored in liver as glycogen, insulin produced by pancreas
116
Explain the influencing factors of enzymes
Optimum temp. and pH range above optimum will denature and activity will suddenly drop Increasing temp. increases energy of collisions, internal energy of reactants and number of collisions
117
What are lipids?
``` Diverse class of insoluble compounds that don't form polymers Are hydrophobic (mostly hydrocarbons) and soluble in organic solvents (ether, acetone, chloroform) ```
118
Give examples of lipids
Fats, oils, fatty acids, triacylglycerols, glycolipids, phospholipids, steroids
119
What is the main function of fatty acids?
Catabolised generating ATP or used to synthesise triglycerides and phospholipids
120
Main function of triglycerides?
Energy storage, protection, insulation
121
Phospholipids main function?
PM
122
Main function of steroids
Component of many hormones, cholesterol
123
Describe the structure of fatty acids
Long hydrocarbon chain with terminal carboxylic acid group Hydrocarbon chain: saturated (no double bonds), monounsaturated (1 C=C), polyunsaturated (2+ C=C) Unsaturation causes kink in chain All naturally occurring unsaturated fats are in cis formation whereas trans unsaturated fats found in manufacture of food
124
Compare saturated and unsaturated fats
Palmitic (C16) is a saturated fat, MP 69.9 Oleic (C18) is monounsaturated, MP 13.4 - C=C makes packing of molecule difficult Most animal fats are saturated whereas most fish and plant fats are unsaturated
125
What is glycerol and what is its importance?
Three C substance that forms backbone of fatty acids in fats | Important component of triglycerides and phospholipids
126
What is triglyceride and describe its structure
Main component of vegetable oil and animal fats formed from the esterification of 3 fatty acids with glycerol Has chemical structure CH2COOHR-CHCOOHR'-CH2COOHR"; Rs are long alkyl groups The fatty acids can be all same, different or 2 the same
127
What is the importance of triglycerides?
Metabolism: contain 2X energy as carbs and proteins Storage and transport form of fats High levels linked to atherosclerosis (heart disease, stroke)
128
What is the role of adipocytes and adipose tissue?
Adipocytes specialised for synthesis and storage of triglycerides Found in subcutaneous layer and in abdominal layer Subcutaneous fat provides insulation
129
What is lipolysis?
Breakdown of triglycerides into glycerol and fatty acids with release of energy Fatty acids released into blood, circulate body
130
Describe the catabolism of glycerol
Converted to glyceraldehyde 3-P and then glucose OR enter TCA depending on ATP supply
131
Describe the catabolism of fatty acids
Enzymes remove 2C atoms at a time to acetyl CoA to enter TCA
132
Describe the process of FA activation
Acetyl-CoA synthases esterify long chain FAs to acyl-CoA | Is ATP dependant
133
Describe the process of FA oxidation
Acyl-CoA dehydrogenase removes H2 from acyl-CoA, NAD is reduced to NADH2, acetyl-CoA oxidised to trans-enoyl-CoA enoyl-CoA hydratase, hydrates trans-enoyl-CoA to B-hydroxyacyl-CoA B-hydroxyacyl-CoA dehydrogenase oxides B-..-CoA to B-ketoacyl-CoA Acyl-CoAacetyl-transferase moves acetyl forming acyl-CoA (2Cs shorter) + acetyl-CoA
134
What is lipogenesis?
Synthesis of lipids (anabolism) from smaller units Mainly occurs in liver and adipose tissue in conditions of excess sugar as glucose converted to glycogen It doesn't appear to be essential
135
Compare glucose and fructose
Glucose used in cells throughout body, fructose only in liver Glucose converted to glycogen, some to FAs and triglycerides Fructose converted to acetyl them FAs and triglycerides
136
What are essential fatty acids?
FAs that are required in human diet as humans lack specific enzyme so cannot be synthesised by the body
137
What can a deficiency of a-linoleic acid and linoleic acid lead to?
Dry scaly rash, decreased growth (children/infants), susceptibility to infection, poor wound healing Present in variety of foods, represent omega 3 and 6 category of lipid structure
138
Describe the structure of phospholipids
2 FAs and P group attached to glycerol | FAs from hydrophobic tail, P and its attachment form hydrophilic head
139
What is meant by amphipathic?
Molecule with both hydrophobic and hydrophilic groups
140
Describe saturation in phospholipids
1 chain saturated, other not | Degree of saturation alters ability of molecules to pack, affects fluidity
141
What is the function of cholesterol?
Controls permeability of membrane | Makes membrane less flexible due to rigid steroid ring
142
Describe glycolipid structure
2 hydrophobic tails, hydrophilic region with 2+ sugar residues i.e. phospholipids without P
143
What is the function of glycolipids?
Make up 5% of outer monolayer Sugar groups exposed on cell surface protect and modulate membrane function Insulating agents in nerve cells (gangliosides)
144
Describe the structure of steroids
Lipids characterised by C skeleton of 4 fused rings
145
What is the role of steroids?
Cholesterol: high levels cause atherosclerosis Hormones: testosterone, oestrogen, cortisol (synthesised from cholesterol) control metabolism, development of sexual characteristics, immune functions
146
What is a lipoprotein?
Biochemical assembly that contains both proteins and lipids
147
What is the function of lipoproteins?
Transport insoluble lipids in plasma | Non-polar lipids (triglycerides) contained in hydrophobic centre, polar lipids (phospholipids) form coat
148
What are apoproteins?
Protein components of lipoproteins | Interact with cellular receptors and determine the metabolic fate of lipoproteins
149
Explain LDL and HDL
LDLs carry FAs in blood for use by cells but also deposit on artery walls (bad) HDLs carry LDLs away from artery walls (good)
150
What are some of the ways to treat hypercholesrerolemia?
Reduce intake (egg yolk, liver, oily fish) Reduce absorption uptake - zetia, ezetro, niacin Statins - block enzyme in synthesis of cholesterol
151
What are the 2 classifications of carbs?
Simple - monosaccharides | Complex - disaccharide, oligosaccharide(2+), polysaccharide (many)
152
Describe monosaccharides
Simple sugars: can't be converted into smaller molecules by acid hydrolysis 1 sugar, usually colourless, water-soluble, crystalline solids Building blocks of di and polysaccharides
153
Describe the structure of monosaccharides
Generally have formula (CH2)n - deoxyribose is an exception Simple monosaccharides C4-7 called tetroses, pentoses, hexoses, heptoses Exceptions in animals N-acetyl sugars (8C), sialic acid (9,10,11C)
154
What are 2 classifications of monosaccharides?
Aldose and ketose Aldose - -CHO (aldehyde group) Ketose - C=O (ketone group) e.g. aldopentose or ketopentose
155
Describe the structure of glucose in both straight chain and ring
``` C6H12O6 Is an aldose sugar i.e. has -CHO Ring: C1 binds to C5 - C1-O-C5 O enables C atoms to bind to from ring H from C5 OH binds to O on C1, C1 binds to O ```
156
Describe the structure of fructose
C6H12O6 Is a ketose i.e. has C=O on C2 Ring: C2 bonds to C5 H of C5 OH binds to O of C2, C2 binds to O on C5
157
What is stereochemistry?
Study of spatial 3D relations of atoms in molecules
158
What are Fischer projections?
Basic 2D drawing of 3D molecule C1 is always at top Projections drawn to left are ABOVE the ring Projections to right are BELOW the ring
159
Explain D and L sugars
D and L sugars are optical isomers (mirror images of each other) D and L refer to the absolute configuration of asymmetric C furthers away from aldehyde/ketone group OR if OH falls on either LHS/RHS D-glucose is biologically active, OH of C5 falls on RHS
160
What is the structure of D-glucose?
OH of C2,4,5 to right OH of C3 to left L-glucose is opposite
161
What happens in solution of glucose in terms of structure?
Equilibrium favouring ring form established Ring formation creates new chiral centres - C1 in aldoses, C2 in ketoses This increases the number of possible isomeric forms
162
What are isomers of D-glucose called?
Anomers
163
Describe the 2 anomers of D-glucose
Alpha - (new) OH of C1 is TRANS to CH2OH on C5 | Beta - OH of C2 is CIS to CH2OH on C5
164
What is mutarotation?
Interconversion between anomer stereoisomers | Different anomers have different optical rotations
165
What are monosaccharide derivatives?
Simple sugar molecules which contain functional groups as well as OH, either CHO/CO, vary from empirical formula
166
Describe deoxy derivatives
OH replaced by H | e.g. deoxyribose sugar - ribose with OH on C2 replaced by H
167
Describe sugar acid derivatives
OH group oxidised to COOH
168
Describe sugar alcohol derivatives
CO (aldehyde or ketone) reduced to primary/secondary OH
169
Describe phosphorylated sugars
P group attached | Alcoholic group esterified with phosphoric acid
170
What are amino sugars?
Sugar with primary amine group replacing OH | e.g. glucosamine precursor for GAGs (major component of joint cartilage) thus used to treat osteoarthritis
171
Explain the formation of disaccharides
Aldehyde/ketone group reacts with molecules own OH to form ring, then link to C bearing OH on another sugar molecule creating a disaccharide
172
How are monomers linked?
Glycosidic bonds formed when anomeric OH group condenses with alcohol of second monosaccharide Catalysed by hydrolyse (dehydration) to form R-O-R link
173
Describe the structure of sucrose
Glucose and fructose monomers linked by alpha 1,2 linkage
174
What is glycogen?
Polysaccharide that is the principal storage form of glucose found as granules in cytosol Liver cells have highest conc. but muscles have greater total amount
175
Describe the structure of glycogen
``` Highly branched (increases packing) Linear chains of glucose connected by a-1,4 glycosidic linkages with branches attached through a-1,6 links every 10 residues ```
176
What 2 enzymes are required for glycogen degradation and why?
Glycogen phosphorylase to hydrolyse a-1,4 linkages but can only work on linear chains OR a-amylase (digestive) Debranching enzyme to hydrolyse a-1,6 links to straighten out chain
177
Describe the degradation of glycogen
Glycogen phosphorylase breaks glycogen into glucose-1-P but is halted 4 residues from branching point Glycogen debranching enzyme transfers trisaccharide to a-1,4 adjacent a-1,4 link leaving single glucose molecule at a-1,6 GDE hydrolyses remaining glucose molecule so glycogen phosphorylase can continue
178
Describe the structure of starch
(C6H10O5)n 2 polysaccharides monomers: amylose, amylopectin Amylose: glucose monomers linked by a-1,4 links Amylopectin: coiled structure, like glycogen but a-1,6 branch every 24-30 residues
179
What is the function of starch?
Digested by hydrolysis, catalysed by amylases, back to sugar monomers which can be broken down to glucose for energy
180
What is cellulose?
Polymeric polysaccharide of B-glucose monomers
181
What is the function of cellulose?
Primary structural component of cell wall of green plants Lignin and cellulose (lignocellulose) most common biopolymer on earth Only tunicates evolved the ability to create and use cellulose Indigestible by humans so acts as hydrophilic bulking agent for faeces
182
Describe the structure of cellulose
Layered linear chains of B-1,4 linked D-glucose units packed into crystals (myofibrils) Layers linked by H bonds
183
What is lactose?
Disaccharide of B-D-galactose and B-D-glucose linked through B-1,4
184
What are glycosaminoglycans? (GAGs)
Large, pure carbohydrates that are -ve charged, hydrophilic | Polysaccharides present on animal cell surface and in ECM
185
Describe the structure of GAGs
Disaccharide repeating unit containing glucosamine or galactosamine and uronic acid At least one of the sugars has a -ve charged carboxylate or sulphate group - with exception of hyaluronic acid (no sulphate group)
186
What is a glycoprotein?
Macromolecule composed of protein and a carbohydrate which is added in posttranslational modification either at asparagine (N-glycosylation) or hydroxylysine/hydroxyproline/serine/threonine (O-glycosylation)
187
What is the function of glycoproteins?
Assist protein folding or improve stability Immune cell recognition: antibodies (immunoglobulins) interact directly with antigens, moles of major histocompatibility complex (MHC) surface of cells interact with T-cells (adaptive immune response)
188
Explain N and O glycosylation
Glycosylation is the attachment of carbohydrate to AA side chain N: attach to N of amide side chain (asparagine) O: attach to O of OH side chain (hydroxylysine/hydroxyproline/serine/threonine)
189
What are proteoglycans?
Heavily glycosylated glycoproteins - core protein with several GAG chains
190
What are the functions of GAGs?
Structural: ECM and BM Space-filling in cartilage Modifiers/activators of effector proteins (growth factors, proteases)
191
What are the functions of proteoglycans?
Form large complexes in ECM with proteoglycans and fibrous matrix proteins (collagen) Binding of cations and water Regulation of movement of molecules through matrix
192
What is chondroitin sulphate?
Sulphate GAG composed of N-acetyl-galactosamine and glucuronic acid Usually forms part of a proteoglycan
193
What is the function of chondroitin sulphate?
Major structural component in cartilage conferring resistance to compression Dietary supplement for treatment of osteoarthritis
194
What is heparin?
Highly sulphated GAG used as injectable anticoagulant and used for inside of test tubes, renal dialysis machines
195
Describe the structure of peptidoglycan
Crystal lattice of linear chains of NAG and NAM Each NAM has peptide chain usually containing AAs that do not occur in humans thought to protect against attacks by most peptidases
196
Describe the energy balance in humans
Balance between energy intake and energy expenditure
197
Describe the anabolism of glucose
Glucose enters cell, undergoes glycogenesis forming glycogen in liver and muscle cells OR undergo lipogenesis and join FA chain
198
Describe the anabolism of FAs
FAs esterified to triglycerides in adipose tissue
199
Describe the anabolism of AAs
AAs undergo protein synthesis to form proteins in muscle
200
Describe the metabolism of glycogen
Glycogen undergoes glycogenesis forming glucose, undergoes glycolysis to pyruvate converted to acetyl-CoA enters TCA
201
Describe metabolism of triglycerides
Undergo lipolysis forming FAs, undergo B-oxidation to form acetyl-CoA enter TCA
202
Describe protein metabolism
Proteolysis converts to AAs either directly enter TCA or converted to acetyl-CoA
203
Describe glycogen stores and their mobilisation
In liver glycogen converted to glucose-6-P which is converted to glucose which can enter brain or back to glucose-6-P and used by muscles to produce lactate Muscle cells produce glucose 6P then lactate
204
Describe the cori cycle
Lactate produced in muscle cell converted to pyruvate which can enter gluconeogensis to re-form glucose which can be recycled
205
Describe lipid stores and mobilisation
Triglyceride stored in adipose broken down to glycerol and FAs Glycerol undergoes gluconeogenesis forming glucose, enters brain FAs enter muscle or undergo ketogenesis forming ketone bodies utilised by brain or enter muscle
206
Describe protein utilisation
Undergo proteolysis produce AAs which can enter TCA, converted to Acetyl-CoA or undergo transamination (amino group moved) Acetyl-CoA enter TCA or converted to ketone bodies After transamination form pyruvate either enter TCA or gluconeogenesis
207
Describe glucose transport
Enters cells via facilitated diffusion by GLUTs | Uptake increased by increasing GLUTs in PM - insulin or exercise
208
Describe FA transport
Thought to diffuse across PM or may involve FA transporter proteins
209
How is energy stored in cells?
In chemical bonds | When cell has enough energy available it stores it by adding Pi group to ADP forming ATP
210
What are the stages of ATP production?
Digestion Glycolysis TCA
211
Describe digestion
Food stuff digested HCl in stomach Enzymes - mouth, stomach, small intestine Enzymes in lysosomes for internal cell digestion Absorption through cells in SI, enter bloodstream then cells
212
Describe glycolysis
Starts in cytoplasm Glucose broken down to 2 pyruvate molecules 2ATP and NADH produced per pyruvate Pyruvate molecules move to mitochondria where converted to CO2 and 2C acetyl group which attaches to CoA
213
Describe the structure of CoA
8 trimers of lipoamide reductase-transacetylase 6 dimers of dihydrolipoyl dehydrogenase 12 dimers pyruvate decarboxylase
214
What are the functions of the three enzymes in CoA?
Pyruvate decarboxylase - removes CO2 Lipoamide reductase transacetylase - transfer acetyl group Dihydrolipoyl dehydrogenase - reduces NAD
215
What happens in glycolysis in anaerobic conditions?
Fermentation Muscle: pyruvate reduced to lactate reforming NAD+ Yeast: pyruvate reduced forming CO2 and acetaldehyde which is reduced to ethanol reforming NAD+
216
Describe stage 3 of ATP production
Acetyl group enters TCA where it is oxidised to CO2 and large amounts of NADH generated NADH passed along electron transport chain where energy released produces ATP and consumes O2
217
What is oxidative phosphorylation?
ATP formation driven by transfer of electrons from food molecules to molecular O2 Electron ends up on O2, with H+ H2O formed
218
Name the 4 complexes of the electron transport chain
1. NADH dehydrogenase 2. Succinate dehydrogenase 3. Coenzyme Q reductase 4. Cytochrome c reductase
219
What are the roles of the complexes in electron transport chain?
NADH dehydrogenase, succinate dehydrogenase, coenzyme Q reductase pump protons across membrane into intermebrane space making intermembrane increasing acidic Cytochrome c reductase give electron to O2 producing H2O
220
How does the electron transport chain produce ATP?
Due to the high H+ conc. in intermembrane space, protons diffuse down conc. gradient through ATP synthase producing lots of ATP
221
Name and describe the inhibitors of electron transport chain
Rotenone: blocks NADH from being oxidised by NADH dehydrogenase Antimycin A: blocks complex 2 CN or CO: prevent O2 being reduced by cytochrome c reductase
222
What is the role of reactions?
Create order within cells: smaller molecules used to make macromolecules
222
Define catabolism and anabolism
Catabolism: break down of molecules releasing energy Anabolism: construction of complex molecules from simple ones, storage of energy
223
Define free energy
Gibbs free energy (G): measure of energy contained in a molecule due to vibration, rotation, bonds
224
What is delta G?
Changes/difference in free energy | DG = G(products p) - G(reactants)
225
Define exergonic and endergonic
Exergonic: releases energy to surroundings -DG Endergonic: absorbs free energy +DG
226
Define activation energy
Energy difference between reagents and transition state i.e. energy required for reaction to progress
227
How do enzymes work in terms of EA?
Lower the EA allowing larger proportion of random collisions with surrounding molecules to push substrate over EA
228
How do enzymes work?
Bind substrate tightly holding it in a way that facilitates conversion to product
229
Explain coupled reactions
Favourable (oxidisation of glucose) reactions release energy which is captured in chemical form and used to power unfavourable reactions (forming peptide bond) Favourable reactions take place spontaneously whereas unfavourable only occur if coupled
230
What are carrier molecules?
Small proteins that contain 1+ energy-rich covalent bond and diffuse rapidly throughout cell thus carry bind energy from generation to utilisation
231
How do carrier molecules (coenzymes) store their energy?
In easily transferable groups/high-energy electron (easily oxidised/reduced) - ATP, NADH, NADPH
232
Describe the synthesis of a polynucleotide
Nucleoside monophosphate activated by sequential transfer of terminal P from 2 ATP High energy intermediate (nucleoside triphosphate) exists freely until reacts with growing end of R/DNA releasing pyrophosphate Hydrolysis of pyrophosphate to Pi highly favourable, drives overall reaction
233
Explain the limits of ATP
DG of ATP is -7.3kcal/M only drive reaction up to that amount If reaction requires more ATP hydrolysis altered to produce AMP and PPi (pyro) which is hydrolysed producing large amounts of free energy
234
What is the importance of enzyme inhibitors?
Info about shape of AS and AA residues at AS Info about chemical mechanism Info about regulation/control of metabolic pathway Aide drug design
235
What are the 2 broad classifications of inhibitors?
Reversible Irreversible: usually involves formation or breaking of covalent bonds - enzyme forms covalent bond with AS so cannot be removed
236
What are the 3 types of reversible inhibitors?
Competitive Non-competitive Uncompetitive
237
Explain irreversible inhibition
Inhibitor forms covalent bond with AS of enzyme so is permanently attached thus permanently inactivates enzyme e.g. diisopropylphosphofluoridate prototype for nerve gas sarin, permanently inactivates serine proteases
238
Explain competitive inhibition
Inhibitor competes with substrate to bind on AS Inhibitor and substrate have similar structures ONLY binds to enzyme NOT ES complex
239
Explain the effect of competitive inhibitors on Vmax and Km
Reduces amount of free enzyme available for substrate binding (forms EI complex) thus Km increased, Vmax unchanged but requires more substrate to reach
240
Give an example of competitive inhibition
Succinate is converted to fumarate by succinate dehydrogenase Malonate is a competitive inhibitor for this reaction
241
How is competitive inhibition reversed?
Increase conc. of substrate to overcome reduced affinity
242
Explain non-competitive inhibition
Inhibitor binds to separate, distinct binding site causing SLIGHT conformation change Can bind to E or ES and from ESI complex which is inactive
243
Explain the effect on Vmax and Km of non-competitive inhibition
As substrate can still bind Km remains constant | As ESI inactive Vmax reduced
244
Give an example of non-competitive inhibition
Fructose-1,6-diphosphate converted to fructose-6-phosphate by fructose-1,6-bisphosphatase which is inhibited by AMP (binds to separate site) and no fructose-6P produced
245
Explain uncompetitive inhibition
Binding of substrate allows inhibitor to bind forming inactive ESI complex Inhibitor ONLY binds to ES
246
Explain the effect of uncompetitive inhibition on Vmax and Km
Vmax decreased as enzyme inhibited | Km also reduced as creates better ES binding as only binds to ES (due to equilibrium and Le Chatelier's Principle)
247
What are allosteric modulators?
Substances which can regulate enzyme activity
248
Explain the 2 types of allosteric modulators
Positive: increase enzyme activity, binds to allosteric site causing conformational change to enhance substrate binding Negative: decrease activity, binds to site causing conformational change to decrease substrate binding
249
What 2 hormones are responsible for regulation of glucose levels?
Insulin: promotes uptake and conversion to glycogen Glucagon: promotes breakdown of stored glycogen to glucose
250
Name the 2 conditions caused by excess and lack of glucose
Hyperglycaemia: excess glucose, hallmark of diabetes, glucosuria (glucose toxicity) Hypoglycaemia: lack of glucose, loss of cognitive function, coma, permanent brain damage
251
How is glucose transported into cells in the body?
Intestine: uptake from lumen to epithelial requires active transport Body: blood to cells (muscle, liver, adipose) passive or facilitated diffusion
252
How is glucose uptake mediated?
GLUT transporters mediate glucose transport into liver, adipose, muscle tissues
253
Describe GLUTS 1-4
GLUT1+3: PM throughout body, low Km 1mM (high affinity), maintain basal blood glucose 3-6mM GLUT2: liver, pancreatic cells, high Km 15-20mM, (low affinity as liver stores, pancreas produces insulin in high conc) GLUT4: muscle, adipose, low Km, insulin sensitive (phosphorylated by Metformin (anti-diabetic) increasing insulin sensitivity)
254
How is glucose uptake regulate by insulin and exercise?
Uptake into muscle and adipose increased by insulin which increases no. of GLUT4 transporters in PM (GLUT4 containing vesicles fuse with PM) Insulin resistance associated with fewer GLUT4 transporters Exercise recruits GLUT4 transporters to PM in muscle
255
Describe the alternative fates of glucose
Converted to glucose-6P either enter pentose phosphate pathway produce 5C sugar OR glycolysised to pyruvate (gluconeogenesis reproduce glucose-6P)
256
Explain the role of hexokinase in glycolysis
Found in most cells throughout body, phosphorylates glucose to glucose-6P (1st step of glycolysis) Low Km Allosteric inhibition by own product (glucose-6P) Inhibition of HK causes increase in intracellular glucose inhibiting GLUT transporter
257
Explain the role of glucokinase in glycolysis
Phosphorylates glucose in liver and pancreatic B cells Higher Km - only active when glucose levels are high In B cells acts as glucose sensors for insulin secretion Not inhibited by glucose-6P
258
Outline the 10 steps of glycolysis
``` G-glucose G-glucose-6P F-fructose-6P F-fructose-1,6-bisphosphate G-glyceraldehyde-3P (+ dihydroxyacetone-P) G-glyceraldehyde-3P B-1,3-bisphosphoglycerate P-3-phosphoglycerate P-2-phosphoglycerate P-phosphoenolpyruvate P-pyruvate ``` ``` H-hexokinase P-phosphoglucose isomerase P-phosphofructokinase A-aldolase T-triosephosphate isomerase G-glyceraldehyde-3P dehydrogenase P-phosphoglycerate kinase P-phosphoglycerate mutase E-enolase P-pyruvate kinase ```
259
Explain how phosphofructokinase 1 regulates glycolysis
High ATP conc. allosterically inhibits PFK1 by binding, promotes tense conformation with low affinity for fructose-6P PFK2 convert fructose-6P to fructose-2,6-bisP (+ ADP) high levels of fructose-2,6-bisP relieves inhibition High levels of citrate (1st intermediate TCA) inhibits as confers ATP already present ADP, AMP(extensive ATP hydrolysis) relieve inhibition
260
Define kinases and mutases
Kinase: phosphorylates i.e. transfers PO4 from ATP to substrate Mutase: transfer PO4 from 1C to another within molecule
261
Describe fermentation
Anaerobic organisms lack respiratory chain, NADH reoxidised as pyruvate converted to more reduced compound Some organisms convert pyruvate to ethanol oxidising NADH in reaction catalysed by alcohol dehydrogenase
262
Explain how NADH enters the matrix of mitochondria
Oxaloacetate reduced to malate oxidising NADH Malate enters matrix is oxidised to oxaloacetate reducing NAD+ Oxaloacetate converted to aspartate by glutamate forming a-ketoglutarate Aspartate leaves matrix, reacts with a-ketoglutarate reforming oxaloacetate and glutamate
263
Describe galactose metabolism
Gladstone phosphorylated to galactose-1P by galactokinase UDP-glucose reacts with galactose-1P converting to glucose-1P and forming UDP-galactose Glucose-1P P group moved by phosphoglucomutase to glucose-6P
264
What is the importance of Ca?
Bone: provide structural integrity of skeleton | Biochemical processes: neuromuscular excitability, blood coagulation, hormonal secretion, enzymatic regulation
265
Why must Ca conc. be maintained?
As has role in so many processes extra and intracellular conc. must be maintained
266
Describe the regulation of intracellular [Ca]
Stored in mitochondria and ER 'Pump-leak' transport system: Ca leaks into cytoplasmic compartment, actively pumped into storage sites in organelles to shift away from cytosolic pools
267
What are the 3 fractions of Ca in serum?
Ionised - 50% Protein-bound - 40% Complexed to serum constituents - 10%
268
What protein is the majority of protein-bound Ca bound to?
Albumin -90%, binding is pH dependent | Rest is bound to globulins
269
What 2 molecules is Ca complexed to?
Citrate | Phosphate
270
Describe the effect of acute alkalosis on Ca binding
Inc. Ca binding, dec. ionised Ca | Causes inc. neural excitability and prone to seizures due to low ionised Ca in ECF causing inc. permeability to Na+
271
Describe Ca turnover
1000mg intake 350mg absorption to ECF (1000mg) and exchangeable pool (4000mg) 500mg used and retrieved in bone remodelling 1000000mg stored in skeleton 200mg excreted in urine 150mg secreted into gut 800mg excreted in faeces
272
What factors determine the conc. of serum Ca?
Intestinal absorption, renal excretion, bone remodelling
273
Explain +ve and -be Ca balances
+: intestinal Ca absorption exceeds urinary excretion, difference deposited in growing bones -: intestinal absorption less than urinary excretion
274
What are the 3 hormones involved in regulating Ca homeostasis?
Calcitonin Parathyroid hormone Calcitriol
275
How does calcitonin work and what is its effect?
Gs-couple: inc. cAMP, inhibit osteoclast, less Ca resorption, more Ca incorporated into bone tissue Dec. Ca2+ Stimulated by inc. Ca2+ in plasma
276
What is the function of PTH and what are its actions?
Inc. Ca Inc. bone resorption Inhib. renal P reabsorption in proximal tubule - excreted in urine Inc. renal Ca reabsorption in distal tubule Inc. intestinal Ca absorption indirectly by stimulating production of 1,25-dihydroxycholecalciferol
277
What is the function of calcitriol?
PTH-like effect in bone | Mediated effects of PTH absorption of Ca and P by gut
278
Where is calcitonin formed and secreted?
Parafollicular cells of thyroid
279
Where is PTH formed and secreted?
Parathyroid gland
280
How is the secretion of PTH regulated?
Negative feedback: secreted as serum Ca2+ falls
281
How is VitD synthesised?
1. Skin cells convert 7-dehydrocholesterol to pro hormone cholecalciferol (B3) using sunlight 2. Liver then kidney convert pro hormone to active VitD3 (1,25-dihydroxycholecalciferol/dihydroxy-D3)
282
What are the actions of VitD3?
1. Inc. intestinal Ca absorption 2. Inc. intestinal P absorption 3. Inc. renal reabsorption of Ca and P 4. Inc. resorption of bone
283
What are osteomalacia/rickets?
Conditions caused by VitD deficiency leasing to poor bone mineralisation reducing bone mass thus making bones weak
284
What are the 2 types of osteomalacia?
VitD-responsive | VitD-resistant
285
Describe VitD responsive osteomalacia
Caused by deficiency in dietary intake of VitD precursors, inadequate sunlight exposure, malabsorption of Ca
286
Describe the 2 forms of VitD-resistant osteomalacia
Pseudo-VitD: end-organ hyposensitivity | Hereditary VitD-resistant rickets: VitD receptor has poor affinity for its DNA due to mutation in the DNA binding domain
287
What is osteoporosis and what are the 2 types?
Dec. in bone strength Primary: post menopause lose bone rapidly; calcitonin treatment as slows bone resorption Secondary: caused by corticosteroids, Cushing's syndrome, immobilisation, GI disease, alcohol, age senile due to dec. 1,25-dihydroxy-D3 secretion, dec. PTH levels
288
Explain the evidence showing DNA is heredity genetic material
Virulent lysates contain inheritance materials that transformed harmless bacteria to virulent bacteria killing mouse Protein/RNA digestion (protease, ribonuclease) didn't destroy inheritance material - mouse died DNA digestion destroyed inheritance material preventing bacterial transformation thus mouse lived
289
Describe the structure of DNA
Linear polymer of 4 nucleotides - adenine, thymine, guanine, cytosine - each made of base, phosphate group and deoxyribose sugar Nucleotides are linked by phosphodiester bonds and antiparallel strands held in double helix by H bonds between complementary base (AT, GC)
290
What are the 3 DNA conformation?
B A Z | B most prominent but flexible nature of helix allows A Z conformations
291
What is the Central Dogma Theory?
Specific DNA gene sequence gets transcribed into RNA, then translated into unique proteins
292
Describe the process of DNA replication
1. Helicase unwinds double helix forming replication fork 2. Single-stranded DNA binding proteins stabilise SSDNA to prevent rebinding to double helix 3. RNA primase synthesises short fragments of RNA primer required for initiation of DNA synthesis by DNA polymerase 3 4. DNA polymerase 1, DNAse H replace RNA primers with DNA 5. DNA ligase joins Okazaki fragments (lagging strand) to create continuous newly synthesised DNA
293
What are genes?
Basic unit of heredity in all living organisms
294
What is the function of genes?
Encode for proteins essential for biological functions and structures Some produce non-coding RNA molecules that play role in protein biosynthesis and gene regulation
295
What are the molecules that result from gene expression called?
Gene products
296
How do cells read the genome?
DNA doesn't direct protein synthesis directly, use RNA intermediate used as template for protein synthesis Central Dogma of molecular biology
297
Compare DNA and RNA
Sugar: DNA - deoxyribose; RNA - ribose Bases: ATGC; AUGC Structure: double stranded helix; single strand (siRNA is double)
298
Describe the process of transcription
1. Small portion of DNA unwound 2. Only 1 of DNA strands acts as RNA template 3. RNA chain produced called transcript 4. RNA polymerase catalyses formation of phosphodiester bonds, moves stepwise along DNA, unwinding DNA helix to expose new region 5. Extended 1 nucleotide at a time in 5'-3' direction
299
What is the significance of the direction of RNA polymerase?
Determines which DNA strand will be used as template as only work in 5'-3' direction
300
Name and describe the role of the main transcription factors (TF)
TFIID + TBP: binds TATA-box in promoter region near imitation site TFIIA/B: binds TFIID/TBP forming complex for RNA polymerase to bind RNA polymerase: initiates transcription of RNA from DNA, requires ATP
301
What are the 2 types of RNA?
Coding - 4% (mRNA) | Functional - 96%
302
What are the 6 types of functional RNA?
rRNA: component of ribosomes where protein synthesis occurs tRNA: carry AAs to ribosomes Small nuclear: splice hnRNA to mRNA Small nucleolar: chemical modification of rRNA Micro + short interfering: regulate gene expression in eukaryotic cells
303
What are the types of post-transcriptional RNA processing?
End-modification Splicing Cutting Chemical modification
304
How is pre-mRNA converted to mRNA?
snRNPs bind to intron forming loop that pulls exons together | Intron loop is excised and exons spilled together forming mature mRNA
305
What is mRNA translation?
Conversion of info. in mRNA into protein
306
What are the rules of the genetic code?
Sequences of nucleotides in mRNA read in codons (groups of 3) each specifying an AA or stop signal
307
Define what is meant by degenerate
Many codons are redundant as encode the same AA
308
What is the binding of AAs dependent on?
tRNAs that recognise and bind both to codon (via complementary anticodon) and to AA
309
How does the AA bind to tRNA?
Short, single-stranded 3' region of tRNA ribose binds to carboxyl end of AA forming ester bond
310
What is the recognition and binding of correct AA dependent on?
Aminoacyl-tRNA synthetase | Covalently couples each AA to appropriate tRNA molecule
311
How are ribosomes formed?
Ribosomal proteins synthesised in cytoplasm, transported back to nucleolus to bind with rRNA subunit and exported back to cytoplasm
312
Describe the structure of ribosomes
1 small subunit, 1 large subunit Small: provides framework on which tRNA anticodons accurately matched to mRNA codons Large: catalyses formation of peptide bonds linking AAs
313
What is the function of ribosomes?
Maintain the correct reading frame and ensure accuracy
314
What are the 4 binding sites of ribosomes?
1. mRNA 2. Aminoacyl (A): tRNA with bound AA 3. Peptidyl (P): tRNA attached to growing peptide chain 4. Exit (E)
315
Describe the process of protein synthesis
1. Ribosome subunit join near 5' end of mRNA 2. tRNA anticodon binds to complementary mRNA codon at A site bringing AA 3. Ribosome moves towards 3' end, at P site peptide bond forms between existing polypeptide and new AA 4. mRNA moves 1 codon along through small subunit, tRNA ejected at E site, A site free again
316
What is the start codon of protein synthesis?
AUG which special tRNA binds to with methionine - distinct from usually methionine tRNA
317
What is the importance of the start codon?
Dictates reading frame for whole protein Error can lead to frame shift mutation where reading frame is shifted causing all codons to be translated incorrectly forming non-functional protein
318
What are the stop codons and how do they work?
UAA, UAG, UGA Signal binding of release factor Forces peptidyl transferase to bind water freeing carboxyl end of peptide that keeps peptide in ribosome Released into cytoplasm
319
Define somatic and reproductive division
Somatic: cells of body reproduce themselves Reproductive: body produces gametes
320
What is the function of somatic division?
Process by which body grows and replaces dead/damaged cells
321
What is the feel cycle?
Orderly sequence of events in which the cell: duplicates its contents, divides
322
Why must contents must be duplicated for the CC?
So genes can be passed onto next generation
323
What are the 2 major phases of the CC?
Interphase: not diving | Mitotic phase: diving
324
What is interphase?
State of high metabolic activity during which cell does much frowning and replicates DNA and organelles/proteins
325
What are the 3 stages of interphase and state what happens during them
G1: replicates organelles and cytosol S: DNA replication G2: enlarges, synthesises enzymes and proteins for mitosis
326
What is the G0 phase?
Phase most cells are in | If exit cell cycle enter G0, usually cannot re-enter
327
What are the 2 stages of the mitotic phase?
Mitosis: nuclear division Cytokinesis: cell division
328
What are the 4 phases of mitosis and what happens during each?
Prophase: chromatin condense to paired chromatids, nucleolus and nuclear membrane disappear, centrioles move to opp. poles Metaphase: chromatids line up on metaphase plate Anaphase: identical sets of chromosomes move to opp. poles Telophase: nuclear envelope and nucleoli re-appear, chromosomes resume chromatin form
329
When does cytokinesis occur and what happens?
In late anaphase Contractile ring forms cleavage furrow around centre of cell Cytoplasm divided into 2 equal portions
330
What are cyclins and Cdks?
Cyclins are regulatory proteins that activate Cdks | Rb tumour suppressor gene is the major target of Cdks which they phosphorylate at multiple points throughout CC
331
What is meant by G1 restriction point being the 'point of no return'?
Once cell proceeds through point it will complete CC including mitosis and cytokinesis
332
How can inhibitors block the CC?
Inhibitors of Cdk4 (INK4 protein) can prevent phosphorylation of Rb
333
Define hypertrophy and give examples of chronic hypertrophy
Increase in size of cell without division Cirrhosis of liver: hepatocytes become swollen causing narrowing of sinusoids Heart conditions: cardiac myocytes hypertrophy in response to excessive workload
334
What is atrophy?
Decrease in size/number of cells and subsequent decrease in size of tissue/organ Cachexia seen in HIV and cancers
335
Define hyperplasia and give example of chronic
Increase in no of cells due to inc. in cell division Psoriasis in skin Make prostate may lead to benign or malignant tumour
336
What is a cancer?
Cells that divide without control | Usually associated with loss of tissue differentiation and function (anaplasia)
337
What are tumours?
Swelling or lesion formed by abnormal cells | May be cancerous (malignant) and usually spread to other organs (metastasis)
338
How does epidermal growth factor regulate cyclin D1 production?
1. EGF binds receptor, activates G protein 2. kinase cascade will phosphorylate AP1 transcription factor through jun subunit 3. TF binds promoter region of cyclin D1 causing transcription of cyclin D1
339
Define glycolysis
Breakdown of glucose to 2 pyruvate and ATP molecules
340
Define glycogenesis
Assembly of glycogen from excess glucose | Requires ATP, initiated by insulin
341
Define glycogenolysis
Breakdown of glycogen to glucose | Regulated by glucagon
342
Define gluconeogenesis
Synthesis of glucose from metabolites (lactate, pyruvate, glycerol, alanine)
343
What are Islets of Langerhans?
Highly vascularised endocrine glands in the pancreas | High vascularisation allows hormones ready access to circulation
344
What are the 4 secretory cells of the Islets?
a: glucagon B: insulin Delta Digamma
345
What are the functions of insulin?
Regulate blood glucose: signals liver, muscles, adipose to take up glucose; aides cells taking up for energy Signal storage of Glc as Gly when in excess
346
Describe the synthesis of insulin
1. Leader sequence cleaved leaving proinsulin made of A,B,C domains 2. Proteases cleave proinsulin in 2 places releasing peptide C and mature insulin (A,B joined by S-S bond) 3. Packaged into secretory granules containing equimolar amounts of insulin and peptide C 4. Released into extracellular space during secretion
347
Describe the 7 steps of insulin release
1. Glc enters via GLUT2 2. Inc. influx inc. Glc metabolism, inc. [ATP]i 3. Inc. [ATP]i inhib. KATP channel 4. Closed KATP causes depolarisation 5. Depolarisation activates VGCa2+C in PM 6. Influx of Ca2+, inc. Ca2+ induces Ca2+-induced Ca2+ release 7. Ca2+ leads to exocytosis, releasing secretory granules
348
What are the 3 chemical controls of insulin release?
AAs: stim. (inc. uptake and protein synthesis) Keto acids: stim. (inc. uptake to prevent lipid and protein utilisation) Glucose: stim. (feedback loop)
349
What hormones are B cells sensitive to?
Glucagon - inhib. | Somatostatin - inhib
350
Describe the neuronal control of insulin release
PSNS: ACh stim SNS: NA inhib
351
Describe the stim. of Glc disposal postprandial
Insulin binds receptor Insulin signalling pathway activates: effects on protein metabolism, effects on growth, effects on lipid metabolism and translocation of GLUT4 containing vesicles to PM Inc. Glc uptake
352
Describe the inhib. of Glc production postprandial
Insulin blocks Glc production via glycogenolysis and gluconeogenesis PEPCK (inhib gluconeogenesis) and glycogen phosphorylase both targeted Can be acute (dephosphorylation of phosphorylase) or long-term (suppression of PEPCK gene expression)
353
Describe the effects of insulin on adipocyte lipid metabolism
Stim: lipoprotein lipase (LPL), FA uptake, triglyceride esterification Inhib: adipose TAG lipolysis preventing release of FA and glycerol
354
What are the functions of glucagon?
Stim. glycogenolysis Stim. gluconeogenesis Stim. lipolysis
355
Describe how glucagon is regulated
Inc. Glc inhib. release AAs stim. release Stress: AD acts on B receptors on a cells stim. release Insulin inhib. glucagon release
356
How does glucagon stimulate hepatic Glc production?
Stim. gluconeogenesis and glycogenolysis
357
Describe the effects on insulin and glucagon on hepatic lipid homeostasis during fasting
Insulin: suppresses lipin-1 red. VLDL production, carnitine palmitoyltransferase 1 (CPT1) thus inhib. ketogenesis Glucagon: opposite effects thus inc. VLDL production and stim. ketogenesis
358
What is the structure of glycogen?
Polymer of glucose residues linked a(1,4) between molecules and a(1,6) at branching points
359
What does glycogen phosphorylase catalyse?
Gly(n residues) + Pi -> gly(n-1 residues) + glc-1P Catalyses phosphorolytic cleavage of a(1,4) glycosidic linkages Glc-1P released as product
360
What is the prosthetic group for GP?
``` Pyridoxal phosphate (PLP) Phosphate used to break bond ```
361
What is the function of phosphoglucomutase?
Catalyse glc-1P -> glc-6P Glc-6P either enter glycolysis or dephosphorylated for release to blood Free energy = 0, reaction dependent on conc.
362
Explain how glycogen debranching enzyme work
When 4 residues left glycogen phosphorylase stops a(1,4) transglycosylase transfers 3 residues into linear chain a(1,6) glucosidase removes remaining glc
363
Describe liver glycogenolysis and its importance
Glc-6Pase coverts glc-6P to glc Liver gly converted to glc due to presence of glc-6Pase Substitutes for gut during initial stage of starvation as liver glycogen results in direct release of glucose
364
Describe skeletal muscle glycogenolysis
Lack glc-6Pase so glc-6P enters glycolysis Glycogenolysis generates ATP for contraction Lactate generated transported in blood to liver, precursor for gluconeogenesis
365
What are the 2 steps of glycogen synthesis?
Formation of UDP-glc | Glycogen synthesis
366
Describe the formation of UDP-glc
From glc-1P Glc-1P + UTP -> UDP-glc + PPi PPi + H20 -> 2Pi Overall: Glc-1P + UTP -> UDO-glc + 2Pi Spontaneous hydrolysis of P bond in PPi drives reaction Cleavage of PPi only energy cost in glycogenesis
367
Describe glycogen synthesis
Glycogen synthase catalyses Gly(n residues) + UDP-glc -> gly(n+1 residue) + UDP Catalyses transfer of glc to OH C4 of terminal residue of gly chain forming a(1,4) Branching enzyme transfers segment from end of gly to OH C6 of glc residue of gly forming a(1,6) 4 residues from existing branch
368
How is glycogenesis regulated?
``` Modification 1 (phosphorylase) Phosphorylase b (less active) phosphorylated to phosphorylase a (more active) which inhib. glycogenesis Dephosphorylated by phosphoprotein phosphatase-1 ``` ``` Modification 2 (glycogen synthase) GS a (active) phosphorylated to GS b (inactive) inhib. glycogenesis Dephosphorylated by phosphoprotein phosphatase-1 ```
369
Explain how cAMP controls glycogenesis
Glucagon and NA inc. cAMP levels, activates PKA PKA phosphorylates GS to inactive form - inhib. glycogenesis PKA phosphorylates phosphorylase kinase (active) which phosphorylates GP (active) inhib. glycogenesis (enhance glycogenolysis) Insulin inhib. cAMP suppressing glycogenolysis
370
Describe insulin control of glycogenesis
Insulin activates GS phosphatase which dephosphorylates GS (active) Glycogenesis occurs GS kinase 3 and cAMP phosphorylate (inactive) GS, insulin suppresses GSK3, cAMP enhancing glycogenesis
371
What is gluconeogenesis?
Synthesis of glc from non-carb C substrates - lactate, pyruvate, glycerol, glycogenic AAs
372
What is the importance of gluconeogenesis?
During fasting liver glycogen is depleted Gluconeogenesis is source of glucose during this Requires energy and C source
373
What are the 2 important enzymes of gluconeogenesis and where are they found?
Pyruvate carboxylate - mitochondria | Glc-6Pase - ER
374
What is the role of pyruvate carboxylase?
Catalyse pyruvate to oxaloacetate Allosterically activated by acetyl-CoA [oxaloacetate] limiting factor for Krebs cycle In active gluconeogenesis oxaloacetate diverted to form glc, inc. [acetyl-CoA] activates pyruvate carboxylase
375
Outline the steps of gluconeogenesis
Opposite of glycolysis with 4 differences 1. PC: pyruvate -> oxaloacetate 2. PEPCK: oxaloacetate -> phosphoenolpyruvate 3. Enolase: PEP -> 2-phosphoglycerate 4. Phosphoglycerate mutase: 2-phosphoglycerate -> 3-phosphoglycerate 5. Phosphoglycerate kinase: 3-phosphoglycerate -> 1,3-bisphosphoglycerate 6. Glyceraldehyde-3P Dehydrogenase: 1,3-bisphosphoglycerate -> glyceraldehyde-3P 7. Triosphosphate isomerase: glyceraldehyde-3P dihydroxyacetate-P 8. Aldolase: glyceraldehyde-3P + dihydroxyacetate-P -> fructose-1,6-bisP 9. Fructose-1,6-bisPase: fructose-1,6-bisP -> fructose-6P 10. Phosphoglucose isomerase: fructose-6P -> glucose-6P 11. Glc-6Pase: glucose-6P -> glucose
376
How is the pyruvate kinase reaction of glycolysis reversed in gluconeogenesis?
Using pyruvate carboxylase, malate dehydrogenase, PEP carboxykinase Pyruvate enters mitochondria and converted to oxaloacetate by PC MDH catalyses oxaloacetate to malate Malate exits mitochondria converted to oxaloacetate (enters gluconeogenesis) Oxaloacetate converted to PEP by PEPCK and continues gluconeogenesis
377
How is gluconeogenesis regulated?
Glc-6Pase: [Glc-6P] Fructose-1,6-bisPase: AMP, fructose-1,6-bishop (inhib) PC: acetyl-CoA (enhance)
378
Describe the effect of glucagon-cAMP cascade in the liver
Gluconeogenesis stim Glycolysis inhib Glycogenesis inhib Glycogenolysis stim Free glc released to blood
379
Explain how glucose/glycogen can be a C source for gluconeogenesis
Glycolysis forms lactate which is converted to pyruvate by lactate dehydrogenase
380
Explain how proteins can be a C source for gluconeogenesis
Proteolysis forms AAs which are broken down to pyruvate | All AAs except lysine and leucine can supply C
381
Explain how triglyceride can be a C and ATP source
Lipolysis produces glycerol and FAs Glycerol enters hepatic gluconeogenesis FAs oxidised releasing ATP, acetyl-CoA, NADH Acetyl-CoA and NADH inhib. pyruvate dehydrogenase enzyme (prevents loss of CO2, more pyruvate for gluconeogenesis) Acetyl-CoA enhances PC (more oxaloacetate)
382
Outline the 8 steps of the TCA cycle Can I Keep Selling Sex For Money Officer? CAIK Sounds So Fucking Mint
``` Citrate Isocitrate a-ketoglutarate Succinyl-CoA Succinate Fumarate Malate Oxaloacetate ``` ``` Citrate synthase Aconitase Isocitrate dehydrogenase a-ketoglutarate dehydrogenase Succinyl-CoA synthase Succinate dehydrogenase Fumarase Malate dehydrogenase ```
383
What step of TCA is substrate level phosphorylation?
Succinyl-CoA synthase: Succinyl-CoA succinate | GDP -> GTP
384
What are the products of TCA per glucose?
6 NADH2 2 FADH 2 GTP
385
What 3 subunits make pyruvate dehydrogenase enzyme?
1. Pyruvate carboxylase 2. Lipoamide reductase transacetylase 3. Dihydrolipoyl dehydrogenase
386
What are the 3 conditions and fates of acetyl-CoA?
1. Presence of carbs and energy used: metabolised to CO2, NADH, FADH2, GTP - all eventually ATP 2. No energy use: made into fat 3. Energy, no carbs: ketone bodies
387
What 2 steps of TCA are endergonic?
Aconitase: citrate isocitrate | Malate dehydrogenase: malate oxaloacetate
388
What are the 2 regulatory steps in TCA?
Isocitrate dehydrogenase | a-ketoglutarate dehydrogenase
389
What factors stimulate and inhibit the 2 regulatory dehydrogenases?
1. Inc. [ATP/NADH] inhibits | 2. Ca2+ stimulates
390
In the fed state what is the biosynthetic role of TCA?
Excess glucose converted to acetyl-CoA then citrate which is exported from mitochondria ATP and citrate lyase convert citrate to acetyl-CoA and oxaloacetate Acetyl-CoA then enters lipogenic acid and cholesterol synthesis pathways to forms FAs and cholesterol
391
What is the biosynthetic role of TCA in the fasted state?
AAs that can be converted to oxaloacetate yield net glucose synthesis FAs can't be converted as C atoms from acetyl-CoA lost as CO2 Acetyl-CoA can't be converted to pyruvate as reaction irreversible
392
How does FA oxidation block glucose oxidation?
Acetyl-CoA and NADH (produced by FAO) are inhibitors of PDC which converts pyruvate to acetyl-CoA Acetyl-CoA and NADH stimulate PDC kinase to phosphorylate PDC to inactive form
393
What happens to citrate when glucose is ample?
Exported from mitochondria and converted to acetyl-CoA then malonyl-CoA (FA synthesis precursor) Rise in malonyl-CoA inhibits COR-1 and suppresses FAO
394
How do hypoxic events upregulate glycolysis?
Hypoxia-inducible factor (HIF1) transcription factor is stabilised, bind to hypoxia responsive elements in promoter regions including glycolytic enzymes
395
How does chronic HIF action low mitochondrial respiration?
HIF1 downregulates mitochondrial respiration by promoting mitochondria autophagy and suppressing mitochondrial biogenesis May be adaptive mechanism to prevent oxidative stress by restricting production of reactive oxygen species
396
Defined glucogenic and ketogenic
Glucogenic: glucose can be formed from C skeleton Ketogenic: AAs degraded to acetyl-CoA
397
What are the 10 essential AAs? | PVT TIM HALL
Phenylalanine Valine Tryptophan Threonine Isoleucine Methionine Histidine Arginine Leucine Lysine
398
Give an overview of AA metabolism
Ingested protein, biosynthesis and degraded proteins produce AAs AAs produce proteins, purines, pyrimidines, porphyrins Degraded to C skeleton and N N excreted in urea C skeletons to ketogenic/glucogenic products
399
What are the 3 steps to AA degradation?
NH2 group removed Detoxification of amino group Metabolism of C skeleton
400
Outline the urea cycle
Ammonia converted to carbamoyl phosphate which reacts with ornithine to form citruline Citruline converted to arginino-succinate by argininosuccinate synthase and broken down to arginine by argininosuccinate lyase Arginine converted to ornithine releasing urea by arginase
401
What are the general effects of insulin?
``` Start Glucose uptake in muscle, adipose Glycolysis Glycogen synthesis Protein synthesis Uptake of ions ``` ``` Stop Gluconeogenesis Glycogenolysis Lipolysis Ketogenesis Proteolysis ```
402
Compare regulation of blood glucose in fed and fasting states
Fed: insulin secreted by beta cells, stimulates synthesis of metabolic fuel store, lower glucose level Fasting: glucagon secrete by alpha cells, stimulates mobilisation of metabolic fuel store, raises glucose
403
Describe diabetes mellitus
Common endocrine disorder characterised by hyperglycaemia due to defects in insulin production, an absolute or relative lack of insulin or cell resistance to insulin
404
What are the 2 main types of diabetes?
1. Insulin dependent DM/Type 1: IDDM | 2. Non-insulin dependent DM/Type 2: NIDDM
405
What is secondary diabetes mellitus?
Diabetes that arises as consequence of another condition
406
How may secondary diabetes arise?
Pancreatic disease Endocrine disease Drug therapy Insulin receptor abnormality
407
Describe T1 diabetes
Can occur at any age, most common in young Autoimmune destruction of beta cells cause absolute lack of insulin Viral infections may be possible precipitating factor Can be predicted by presence of Islet cell antibody presence in serum
408
Describe T2 diabetes
Occur any age, most common 40-80yo Resistance of tissues to action of insulin, insulin levels normal to high Commonly associated w/ obesity
409
What is type 3 diabetes?
Gestational diabetes | Occurs in 3-10% pregnancies
410
Describe T3 diabetes
Non-diabetics exhibit high blood glucose during pregnancy | Presence of human placental lactogen interferes w/ susceptible insulin receptors causing them to not function properly
411
What are the risks associated w/ T3 diabetes?
Being large for gestational age, low blood sugar, jaundice (in child) Unmanaged: develop T2, higher incidence of pre-eclampsia, C-section Children: obesity and T2 diabetes
412
What predisposing factors are associated w/ T1 diabetes?
Interplay of 3 leading to selective destruction of beta cells 1. Genetic 2. Environmental: diet, toxins, viral 3. Autoimmune: presence of islet antibodies
413
What predisposing factors are associated w/ T2 diabetes?
Complex genetic interactions modified by environmental Genetic: familia aggregation, susceptibility genes Obesity, physical inactivity, stress Adipocyte-derived hormones and cytokines, metabolically active hormones may affect insulin sensitivity
414
What 6 symptoms are associated w/ hyperglycaemia?
1. Polyuria 2. Polydipsia 3. Lassitude 4. Weight loss 5. Polyphagia 6. Blurred vision
415
What complications are associated w/ diabetes?
Leading cause of death and early disability Inc. risk of cardiac, cerebral, peripheral vascular disease Altered hand/foot sensation Inc. risk of periodontal disease
416
What are the acute compilations of diabetes?
1. Hyperglycaemia 2. Diabetic ketoacidosis 3. Hyperglycaemic hyperosmolar non-ketotic coma
417
What are 5 chronic complications of diabetes?
1. Microangiopathy: small blood vessels 2. Macroangiopathy: large blood vessels 3. Neuropathy: 4. Retinopathy: blindness 5. Nephropathy: kidney failure
418
What are the 3 main tests for diabetes?
1. Random blood sample 2. Fasting blood sample 3. Oral glucose tolerance test
419
For random blood glucose, at what level would diabetes be diagnosed?
>/= 11.1 mmol/L
420
For fasting sample what levels of glucose are deemed non-diabetic, impaired fasting glycemic and diabetic?
Non: <6.0 Impaired: 6.1-6.9 Diabetic: >7.0
421
For oral glucose test what glucose levels for fasting and 2 hours later are deemed impaired glucose tolerance and diabetic?
Fasting: impaired <7.0, diabetic >/=7.0 | 2 hour: impaired 7.8-11.0, diabetic >/=11.1
422
Why is HbA1c assessment preferred in monitoring diabetes?
More reliable and accurate assessment of long term control as represent long term blood glucose level during lifetime of protein
423
What is glycation?
Irreversible, enzymatic attachment of glucose to proteins
424
What is HbA1c count?
Measurement of average blood glucose level during preceding 60-90 days before testing Measured as % of total haemoglobin conc.
425
What is a good HbA1c count?
7%
426
What are the 4 predisposing factors of diabetic ketoacidosis?
All in/direct result of lack of insulin 1. Infection 2. Myocardial infarction 3. Trauma 4. Omission of insulin
427
What happens in the absence of insulin?
Muscle and adipose breakdown triglycerides to produce FAs as alternative energy source Inc. lipolysis leads to overproduction of FAs, converted into ketones can cause ketonaemia, metabolic acidosis, ketonuria
428
What happens as glucose transport into tissues decreases?
Hyperglycaemia leading to glycosuria resulting in osmotic diuresis causing loss of water and electrolytes Will result in severe dehydration, cause pre-renal uraemia and may lead to hypovolaemic shock
429
What is the clinical relevance of diabetes?
How will treatment subsequently affect eating: will it lead to hypoglycaemia? Collapsing Hyperglycaemia: loss of consciousness but long process from onset of symptoms to loss of consciousness Hypoglycaemia: may be evident within mins, rapidly lead to loss of consciousness or develop gradually and lead to profession of alteration in consciousness
430
What is a counter regulatory hormone?
A hormone that opposes affect of another hormone i.e. an antagonist
431
What are the 4 main insulin CRHs and what do they respond to?
1. Glucagon 2. AD 3. Cortisol 4. Growth hormone Respond to hypoglycaemia
432
What are the 3 methods for non-diabetic control of hypoglycaemia?
1. Pancreas reduce insulin secretion 2. Alpha cells secrete glucagon, liver release more glucose 3. Adrenal glands secrete AD; liver and kidneys produce more glucose prevents tissues using glucose from bloodstream red. insulin secretion
433
What happens if glucagon and AD fail to return glucose levels to normal?
hGH and cortisol will raise glucose
434
What is the function of hGH?
Childhood: regulate growth rate Adult: maintain muscle and bone mass, tissue repair and healing Secreted by somatotrophs Main function is to stimulation production of insulin-like growth factor by cells in liver, skeletal muscle, cartilage, bone
435
What is the function of ILGF?
Stimulate release of glucose into blood by liver
436
What do hypoglycaemia and hyperglycaemia stimulate the hypothalamus to release?
Hypo: GH-releasing hormone Hyper: GH-inhibiting hormone
437
What are the sections of the adrenal glands?
Cortex: outer 80% Medulla: inner 20%
438
Describe the adrenal cortex
Many LDL receptors Enable cholesterol uptake for steroid hormone synthesis Secrete: glucocorticoids (cortisol), mineralcorticoids (aldosterone), androgens
439
Describe the adrenal medulla
Secrete: catecholamine hormones (NA, AD) and dopamine
440
Describe cortisol
Secreted in response to ACTH from pituitary | -ve feedback loop
441
Describe aldosterone
Stimulated by inc. K+ plasma | Regulates electrolyte balance
442
Describe androgens
Steroid hormones that have masculinising effects
443
What are the 3 hormone systems of the adrenal glands?
1. Glucocorticoids (cortisol) 2. Mineralcorticoids (aldosterone) 3. Androgens
444
What is adrenocorticotrophic hormone?
Regulatory hormone secreted by corticotrophs in ant. pituitary Controls production and secretion of cortisol/glucocorticoids by adrenal cortex Stimulated by CRH from hypothalamus, stress stimuli (trauma, blood glucose) and interleukin-1 from macrophages
445
Describe the action of glucocorticoids/cortisol
Binds to cytosolic receptor and translocated to nucleus upon activation Regulates BP and suppresses inflammation Enhances: gluconeogenesis, adipose tissue lipolysis, muscle proteolysis Inhib: glucose utilisation
446
Describe catecholamine action
Release in response to stress Characterised by inc. O2 consumption and hypermetabolism AD stim: glycogenolysis in liver and muscle; gluconeogenesis in liver Stim: adipose alternative fuel cells to glucose Inc. HR
447
Describe hypofunction of the adrenal glands
Adrenal insufficiency; rare, potentially fatal Signs: lethargy, anorexia, low BP, hypoglycaemia, hyperpigmentation Life threatening Na depletion and possible K retention due to aldosterone deficiency causing low BP Therapy: Na maintenance, hormone replacement
448
What is hyperfunction of adrenal cortex?
Overproduction of cortisol, androgens and aldosterone | Prolonged, excessive exposure can lead to Cushing's syndrome
449
What is Cushing's syndrome?
When ACTH levels don't respond to -ve feedback from high cortisol levels Characterised by remodelling of adipose tissue: deposition on face and trunk, loss from limbs Wasting of skeletal muscle, osteoporosis, slow healing, thinning of skin Excess cortisol may lead to diabetes and hypertension
450
What are tetraiodothryonine and triiodothyronine?
Thyroid hormones 4 and 3 Are thryonines w/ 3/4 iodine atoms Regulated by controlling conversion of 4 to 3 (active from) in target tissues (liver, kidney)
451
Described the mechanism of thyrothropin releasing hormone and thyroid stimulating hormone
TRH controls TSH release TSH stimulates production and secretion of T3 and 4 by thyroid T3and4 control release of TRH
452
What are the 9 general metabolic effects of thyroid hormones?
Inc: basal metabolic rate, body temp, glucose and FA use for ATP synthesis, glucose uptake, lipid and protein turnover Stim: protein synthesis, lipolysis, synthesis of Na/K ATPase Effect on gene expression: slow, long lasting Regulate development and growth of nervous tissue and bones
453
What are the 8 clinical features of hypothyroidism (myxoedema)?
1. Lethargy, tiredness 2. Weight gain 3. Apathy 4. Slow pulse 5. Cold intolerance 6. Constipation 7. Myxoedema 8. Elevated serum TSH
454
What are the 7 clinical features of hyperthyroidism (thyrotoxicosis)?
1. Hyperactivity, insomnia 2. Weight gain 3. Diarrhoea 4. Palpitation 5. Heat intolerance 6. Suppressed TSH, elevated T4 7. Agitation
455
What is body mass index?
Universally accepted classification of obesity | Person's weight (kg) in relation to height (m)
456
What are the BMIs for normal, over weight and the 3 classes of obesity?
``` Normal: 18.5-24.9 Overweight: 25.0-29.9 Class I: 30.0-34.9 Class II: 35.0-39.9 Class III: >40.0 ```
457
Describe the co-morbidity risk changes as weight inc.
``` Normal: no inc. Overweight: inc. Class I: moderate inc. Class II: severe inc. Class III: v severe inc. ```
458
Discuss the advantages of BMI
Low-cost, easy to use Commonly used to determine healthy weight, can compare weight to GP Correlates well w/ amount body fat measured by complex techniques Predicts dangers; as BMI inc. risk inc. Useful screening tool to use @ popn. level, as universally used lots of data from many popns.
459
What is the disadvantage of BMI?
Fails to distinguish between fat and muscle
460
What is obesity?
Excessive accumulation of fat
461
What 2 methods can be used to assess obesity?
1. Waist circumference | 2. Waist-hip ratio
462
Describe waist circumference
Taken at level of iliac crest Men: >40" health risk Women: >35" health risk
463
Describe waist-hip ratio
Waist circumference @ level of L3 over hip circumference @ largest gluteal region Men: >1.0 Women: >0.85
464
Describe the changes in epidemiology and prevalence of obesity
WHO says it is now an epidemic | In last 10yrs inc. by 10-40% in most European countries
465
Describe prevalence of obesity in Britain
Now has highest obesity rate of all Western European counties: 50% overweight, 20% obese >1.1billion adults overweight, 312mil clinically obese 10% children overweight/obese, 17.6mil <5 overweight
466
What are the 4 main factors for cause of obesity?
1. Genes 2. Socio-economic: diet and lifestyle 3. Cultural 4. Psychological and medical
467
What is the evidence for genes playing a role in obesity?
Adults who were adopted as children have weight closer to biological parents Monozygotic twins show much stronger correlation in weight than dizygotic twins
468
Describe the socio-economic factors in obesity
Diet Inc. energy dense foods: animal fats Dec. complex carbs: fibres, coarse grains Inc. alcohol, salt ``` Lifestyle Affluent life w/ less physical activity Car: drive instead of walk TV/games: long time sitting/watching Energy/time saving devices: red. manual labour in home ```
469
How do cultural factors play a role in obesity?
In some countries big is attractive and sign of health and prosperity
470
Describe the psychological and medical factors contributing obesity
Psychological: eat in response to -ve emotions; sadness, anger, boredom Conditions: depression, hypothyroidism, chromosomal anomalies Drugs: corticosteroids, antidepressants, antipsychotics, B-blockers, oral contraceptive, oral hypoglycaemic agents, insulin, antihistamines
471
What are the 9 possible effects of obesity?
1. Hypertension 2. Stroke 3. T2 diabetes 4. Cancer: endometrium, breast, prostate, colon 5. CV mortality 6. Respiratory diseases, sleep-apnea 7. Osteoarthritis 8. Gallbladder disease 9. Metabolic syndrome
472
What are the 2 main types of obesity?
1. Intra-abdominal/visceral | 2. Lower body/external
473
What are the 6 main CV diseases associated with obesity?
1. Hypertension 2. Atherosclerosis 3. L ventricle hypertrophy 4. Cardiac necrosis 5. Cardiac arrhythmias 6. Heart attack
474
How does obesity cause hypertension?
Inc. body mass associated w/: Inc. blood vol. and viscosity Inc. angiotensinogen release from adipocytes Inc. cholesterol and BP
475
What effect does atherosclerosis have on the heart?
Inc. workload
476
What affect does inc. workload have on the heart?
L ventricle hypertrophy
477
What happens when heart workload continues to inc.?
Coronary arteries unable to sustain heart Ischaemia: lack of blood Unable to manifest during high demand Heart loses elasticity: unable to relax completely, dec. filling, dec. blood pumped around body
478
What is congestive heart failure?
Inability of heart to contract properly
479
Explain how obesity can lead to T2 diabetes
Insulin secreted in response to intake of food Prolonged periods of food intake causes constant production of insulin Cellular insulin receptors are down regulated leading to insulin resistance High levels of FAs and glucose in blood Depletion of glucose reserves as glucose not transported Person feels hungry and eats more
480
What are the 5 methods of treatment of obesity?
1. Dietary modifications 2. Behavioural modifications 3. Physical activity 4. Pharmacological 5. Surgery
481
Describe dietary modifications for the treatment of obesity
Nutritionally balanced, low calorie Inc.: fruit, veg, whole grains, nuts Dec.: fatty, sugary foods
482
Describe some behavioural modifications to treat obesity
Keep food diary: time, place, activity, emotions; find link to period of eating/inactivity Help to avoid eating when in feet, watching TV, playing games etc Encouraged to eat home cooked meals and walk rather than use car
483
When should pharmacological treatment of obesity be considered?
18-75yrs: BMI >30 BMI >27 w/ pre-existing risk factor: hypertension, diabetes, obstructive sleep apnoea, cardiac disease BMI >30 and 3 months care not red. weight
484
What 2 drugs are licensed to be used in treatment of obesity?
1. Orlistat | 2. Sibutramine
485
Describe orlistat
Prevents fat digestion and absorption by binding to GI lipase Useful for those w/ high fat diet
486
Describe sibutramine
Red. appetite and inc. thermogenesis | Useful for those who can't control appetite
487
What must be taken into consideration when a patient is on pharmacological treatments of obesity?
Shouldn't be sole therapy Must be strictly and regularly monitored: discontinued if weight loss <5% after 12ws or weight gain recurs Shouldn't be on longer than year, never more than 2 years
488
Describe surgical treatment of obesity
Only in severe cases: BMI >40 2 accepted procedures: gastroplasty, gastric bypass Both red. stomach to small pouch to limit amount of food that can be consumed
489
Describe vitamins
Class of organic compounds categorised as essential nutrient Required for normal function, growth and maintenance Essential for several enzymatic process in human metabolism Are cofactors: don't do anything themselves
490
What are the 2 classes of vitamins?
1. Fat soluble: A D E K | 2. Water soluble: B complexes, C
491
Describe water soluble vitamins
``` Source: fruits, vegs, grains, meat Absorption: directly into bloodstream Storage: circulating freely, not stored in body Excretion: excess in urine Toxicity: rare, possible w/ supplements ```
492
Describe fat soluble vitamins
``` Source: fats and oils in food Absorption: w/ lipids through lymphatic system Storage: in fat and liver Excretion: not easily excreted Toxicity: easily reached ```
493
Describe the sources, RDA and toxicity of vit A
Source: meat, liver, diary products Retinol - active form yellow, red, green fruits and vegetables; Carotene - precursor RDA men: 0.7mg/day; women: 0.6mg/day Toxicity: >1.5mg/day Painful joint, anorexia and/or vomiting, liver damage, fatigue, loss of hair
494
What are the 4 functions of vit A?
1. Promote vision: retinal needed in rhodopsin 2. Protein synthesis and cell differentiation 3. Reproduction and growth 4. Bone growth remodelling
495
What are the 5 ocular and 3 extra-ocular effects of vit A deficiency?
Ocular 1. Night blindness 2. Conjunctival xerosis 3. Bitot's spots 4. Corneal xerosis 5. Keratomalacia Extra-ocular 1. Retarded growth 2. Skin disorders 3. Effect on bone
496
Describe Bitot's spots, conjunctival xerosis and keratomalacia
Bitot's spots: foamy whitish cheese-like tissue spots, cause severe dryness Conjunctival xerosis: conjunctiva becomes dry and non-wettable, appears muddy and wrinkled Keratomalacia: cornea becomes soft, may burst open, if eye collapses vision lost
497
What is carotenemia?
Impairment of conversion of carotene to Vit A due to inborn metabolic error or hepatic disease Generalised yellowish skin and mucosa Excessive deposition of carotene due to high intake of carotene containing foods
498
What are the 5 oral manifestations of vit A?
1. Xerostomia 2. Altered taste 3. Gingival hypertrophy 4. Dec. ameloblast and odontoblast formation 5. Disrupted enamel formation, irregular tubular dentine formation
499
What is unique about Vit d?
Only fat soluble vitamin humans can synthesise
500
What are vit D3 and D2?
D3: cholecalciferol D2: ergosterol
501
Describe the metabolic synthesis of vit D3
Cholesterol converted to 7-dehydrocholesterol UV rays convert 7DC to cholecalciferol which is then hydrolysed in kidney and liver to active 1,25-dihydroxycholecalciferol
502
What are the dietary sources of vit D3?
``` Cheese Butter Margarine Fish Fortified milk and cereals ```
503
What are the RDAs for vit D?
Pregnant/breastfeeding/>65: 0.01mg/d | 6m-5y: 0.007-0.0085mg/d
504
What are the 7 signs and 2 complications of vit D toxicity?
1. Constipation 2. Anorexia 3. Fatigue 4. Muscle weakness 5. Irritability 6. Vomiting 7. Dehydration Complications 1. Kidney stones 2. Kidney failure
505
What are the 5 functions of vit D?
1. Ca and K balance 2. Bone and tooth development: enhance Ca absorption in gut and renal tubules 3. BP regulation 4. Immunity 5. Cell differentiation
506
What are the affects of vit D deficiency?
Rickets: dec. Ca, poor calcification, deformed bones Osteomalacia: post-menopause, bone pain, weak muscle Inc. risk of osteoporosis
507
What are the 4 oral manifestations of vit D deficiency?
1. Teeth: developmental abnormalities in enamel and dentine 2. Higher risk of caries 3. Enamel hypoplasia 4. Pulp: high horns, large chamber, delayed closure of root apices
508
What are the 2 types of vitK and their sources?
K1: plant; spinach, cabbage, broccoli, cauliflower, wheat germ, tomatoes, potatoes, carrots K2: synthesised by intestinal bacteria from milk, fish, meat
509
What is the RDA for vitK?
0.001 mg/d per kg weight
510
What are the 2 functions of vitK?
1. Production of blood clotting factors II, V, VII, IX, X | 2. Bone mineralisation: VitK-dependent proteins; osteocalcin, matrix Gla protein, protein S role in matrix formation
511
What are the effects of vitK deficiency?
Inc. prothrombin time and risk of haemorrhage | Bone deformation
512
What is the oral manifestation of vitK deficiency?
Uncontrollable gingival/mucosal bleeding
513
What is VitE? Generally describe function and how it works
Family of 8 naturally occurring compounds Powerful antioxidant, present in anti ageing products Intercepts free radicals, prevents destruction of cell membrane
514
What are the sources of VitE?
Egg, fish, liver, butter | Soybean, palm oil, sunflower, corn, olive, nuts, green leafy veg, whole grain
515
What is the RDA for vitE?
Men: 4mg/d Women: 3mg/d
516
What is the function of vitE?
Promote vasodilation Inhibit platelet aggregation Prevent atherosclerosis by preventing oxidation of LDLs
517
What are the effects of a VitE deficiency?
Premature ageing: hair, nails, skin Inc. risk of CVD Degenerative changes in blood capillaries
518
Name the B complex vitamins
``` B1: thiamin B2: riboflavin B3: niacin B5: pantothenic acid B6: pyridoxamine B12: cobalamin Biotin Folic acid ```
519
What are the sources of vitBs?
Yeast, grain, rice, fish, veg, meat
520
What is the effect of toxicity of B6?
>5.0mg/d Nerve damage, difficulty walking Numbness in feet and hands
521
What are the 4 functions of vit Bs?
1. Co-enzymes 2. Energy metabolism: B1-6 and biotin 3. RBC synthesis: folate, B12 4. Homocysteine metabolism: folate, B6 and 12
522
What is the effect of B1 deficiency?
Beriberi: after 10 days Weakness, nerve degeneration, irritability, poor leg/arm coordination, loss of nerve transmission Oedema, enlarged heart, heart failure Due to poor glucose metabolism
523
What is the effect of B2 deficiency?
Ariboflavinosis: occurs within 2 months Glossitis, cheilosis, stomatitis, nervous system disorder
524
What does B3 deficiency cause?
Pellagra | Scaly sores, mucosal changes and mental syndrome
525
What does B6 deficiency result in?
``` Depression Nerve irritation Skin disorders Vomiting Impaired immune system ```
526
What does B12 deficiency cause?
Megaloblastic anaemia | Large and irregular RBCs
527
What oral manifestations do vit B deficiencies result in?
B2: glossitis, stomatitis, cheilosis B12: aphthous ulcer
528
What are the sources of vitC in humans?
Citric fruits
529
What is the RDA for vit C?
40 mg/d
530
What 3 things does toxicity of vit C result in?
>1000 mg/d 1. Stomach pains 2. Diarrhoea 3. Flatulence
531
What are the 5 functions of vit C?
1. Antioxidant 2. Enhance iron absorption 3. Synthesis of collagen 4. Immune: reduce cold duration by 1 day 5. Wound healing
532
What does vit C deficiency cause?
Scurvy: 20-40 day deficient Fatigue, pinpoint haemorrhages Bleeding gums and joints
533
What are the oral manifestations of vit C deficiency?
Loosening of teeth and tooth loss | Gum bleeding, gingivitis
534
What are the 3 most important trance minerals?
1. Iodine: thyroid function 2. Iron: haemoglobin 3. Fluoride: bone and teeth
535
What are the 2 most important major minerals?
1. Phosphorus: DNA | 2. Calcium: bones
536
What are the 5 sources of fluoride?
1. Toothpaste 2. Fluoridated water 3. Mouthwash 4. Food processed w/ fluoridated water 5. Fluoride supplements
537
What is the function of fluoride?
Anti-cariogenic: prevent bacterial adhesion suppress cariogenic bacteria change enamel crystalline structure
538
Describe the changes in enamel crystalline structure due to fluoride
HA -> FA Larger crystals Higher pKa to dissolve
539
What is the result of fluoride toxicity?
Fluorosis Chronic Mottled enamel w/ scattered, irregular white flecks
540
Define inherited metabolic disorder
Metabolism disorder caused by mutation in gene that codes for enzyme resulting in enzyme deficiency and breakdown of metabolic pathway
541
What are the 6 clinical presentations in neonates of IEMs and 5 in young children?
1. Vomiting 2. Seizures 3. Irritability 4. Poor feeding 5. Breathing disorder 6. Abnormal tone 1. Recurring vomiting 2. Dysmorphic features: characteristic facial expression 3. Mental retardation 4. Seizures 5. Developmental delay: milestones
542
What are the 7 categories of IEMs?
1. AA metabolism disorders 2. Carbohydrate metabolism disorders 3. FAO disorders 4. Lysosomal storage disorders 5. Peroxisomal disorders 6. Urea cycle disorders 7. Mitochondrial disorders
543
What is Von Gierke's disease?
IEM characterised by deficiency of glucose-6-phosphatase Renders glycogen stores of body inaccessible Lack free glucose Glucose synthesis from glucose-6-phosphate via gluconeogenesis hampered
544
What are the affects of Von Gierke's disease?
1. Hypoglycaemia 2. Lactic acidosis 3. Hepatomegaly
545
Describe galactosaemia
Deficiency of galactose-1P uridyltransferase | Converts galactose-1P to glucose-1P which is subsequently converted to 6P and enters glycolysis
546
What are the effects of galactosaemia?
Child unable to utilise galactose component of lactose in milk Accumulation of galactose-1P in blood, diarrhoea, vomiting, mental retardation, develop cataracts
547
What is the result of a deficiency of liver fructokinase or fructose-1P aldolase?
Fructokinase: convert fructose to fructose-1P Fructose-1P aldolase: fructose-1P to glyceraldehyde Fructose intolerance Results in an accumulation of fructose-1P which inhibits both glycogenolysis and gluconeogenesis leading to hypoglycaemia
548
What are 2 AA metabolism disorders?
Alkaptonuria: black urine | Maple syrup urine disease
549
Describe alkaptonuria
Defect in breakdown of tyrosine and phenylalanine Causes accumulation of homogentisic acid which is excreted in urine and oxidises on standing giving urine black colour This can lead to arthritis due to build up in cartilage
550
Describe maple syrup urine disease
Defect in branched AA metabolism causing accumulation of keto-acids in urine If left unmanaged can lead to physical and mental retardation
551
Describe phenylketonuria
Defect in phenylalanine hydroxylase causes impaired conversion of phenylalanine to tyrosine Phenylalanine accumulates in blood and excreted in urine (aminoaciduria)
552
What are the signs of phenylketonuria?
Irritability Vomiting Mental retardation Red. melanin formation
553
What are the 6 presentations of phenylketonuria?
1. Mental retardation 2. Hypopigmentation 3. Developmental delay 4. Musty odour 5. Autism 6. Epilepsy
554
What is familial hypercholesterolaemia?
Disorder caused by red. number functional LDL receptors in liver
555
What are the 3 effects of hypercholesterolaemia and treatment options?
1. Premature coronary heart disease 2. Tendon xanthomas 3. Severe hypercholesterolaemia Modify diet, fibrates, statins, bile acid binding resins