foundations_-_assessment_2_20130906004532 Flashcards
(151 cards)
2
Q
Define triacylglycerides.
A
Fatty acids consumed in the diet and synthesized de novo are stored in adipocytes
3
Q
Describe fatty acid transport in the fasted state.
A
- Stress hormones signal hormone sensitive lipase (inhibited by insulin)
- Lipase cuts fatty acid
- Fatty acid leaves cell with protein serum albumin
- Circulates until it finds a tissue needing to do work.*Dietary fatty acids are transported around with particles ex. LDL, HDL, and chylomicrons.
4
Q
Why do unsaturated fats have a lower melting point than saturated fats?
A
Double bonds reduces amount of degrees of freedom.
5
Q
What is the first step of beta oxidation?
A
Put a CoA ‘handle’ on fatty acid so enzymes can grab it.
6
Q
How does palimtoylCoA cross the impermeable inner mitochondrial matrix?
A
Carnitine shuttle, catalzyed by carnitine:palmitoyl-transferase I (CPT I). Uses antiporter, fatty acylcarnitine goes in, carnitine goes out.
7
Q
What is ACC?
A
ACC is Acetyl CoA Carboxylase that converts acetyl CoA to malonyl CoA. It is the enzyme that regulates CPT I. AMP inhibits (thus allowing Beta oxidation to continue). Insulin activates (thus inhibiting beta oxidation).
8
Q
Describe the major fatty acid catabolism regulator.
A
Carnitine: palmitoylr-transferase I (CPT I). Malonyl CoA is an allosteric inhibitor of CPT I. Insulin and AMP regulate production of malonyl CoA.
9
Q
Fun fact.
A
When a catabolic pathway is turned on, corresponding anabolic pathway is turned off.
10
Q
Define CPT II deficiency.
A
Inherited autosomal recessive disorder of lipid metabolism. Can’t make fatty acyl CoA in mitochondrial matrix. Buildup of fatty acylcarnitine.1. Adult onset: muscle pain, weakness, myoglobinuria after prolonged exercise or fasting.2. Neonatal onset, irritability FTT, often fatal3. Infant onset Irritability, FTT, often fatal
11
Q
What would you see accumulating in the blood serum in the case of a CPT I patient?
A
Fatty acyl CoA.
12
Q
Describe a cycle of beta oxidation of long chain fatty acids.
A
Two carbons of the fatty acid chain are oxidized to acetyl-CoA which goes to the TCA. Iterative process. 4 steps per cycle (OHOC).1. Oxidation2. Hydration3. Oxidation4. Carbon-carbon bond cleavage
13
Q
What two products do you get at the end of long chain fatty acid beta oxidation?
A
2 Acetyl-CoA.
14
Q
Describe medium chain acyl-CoA dehydrogenase deficiency (MDAC).
A
Infants present with Reye Syndrome:-Fasting hypoketotic hypoglycemia-hepatic encephalopathy (can’t handle NH4)-SIDSDiagnosed by:-lipid profile in blood-ID of mutationsPrognosis:-ID B4 severe hypoglycemia, not bad..fasting tolerance improves with age
15
Q
Define Jamaican vomiting sickness.
A
Similar symptoms to MCAD. Experience after eating unripe ackee fruit which contain hypoglycin, potent inhibitor of acyl-CoA-dehydrogenase. Usuually not fatal.
16
Q
What enzyme converts cis double bonds (dietary fatty acids predominately in cis) to trans configuration?
A
Enoyl CoA isomerase. Only trans double bonds can be accepted by enoyl CoA hydratase. Requires energy, which is why saturated fatty acids have a higher energy yield than unsaturated fatty acids.
17
Q
What happens to odd chain length fatty acids?
A
Beta oxidation occurs normally until chain is 5 carbons long. Then, thiolase makes one molecule of acetyl CoA, and one propionyl CoA.
18
Q
How do branched chain fatty acids get broken down?
A
In peroxisome. Example: In the breakdown of phytanic acid, first the α-carbon is oxidized to CO2. Then β-oxidation occurs, alternately releasing propionyl CoA and acetyl CoA�.
19
Q
Describe several key tissues metabolic needs in relation to glucose and ketones.
A
RBC: absolutely dependent on glucose
Brain: prefers glucose, can’t use fatty acids. Can use ketone bodies.
Skeletal muscle: glucose, fatty acids, ketones, amino acids
20
Q
Where does very long chain fatty acid oxidation take place?
A
Takes place in peroxisomes until they are short enough to be transported to mitochondria.
21
Q
What are the two ketone bodies and the exhaled byproduct?
A
3-hydroxybutyrate and acetoacetate.Acetone is exhaled.
22
Q
Define ketoacidosis.
A
Depression of blood pH by excessive ketone body production. Can be caused by:-starvation-diabetesOften a compensation for hypoglycemia. If patient has hypoglycemia but no elevated ketone bodies, suggests a defect in fatty acid metabolism.
23
Q
What are some key differences between nuclear DNA and mitochondrial DNA (mtDNA)?
A
- Mitochondrial DNA encodes for more only about 13 key genes.
- Mitchondrial DNA uses TFAM instead of histones.
- Mitochondrial DNA polymerase isn’t as good at repairing (mitochondrial DNA are hypermutable due in part to higher concentrations of reactive oxygen species, which increases with age).
25
Q
What is the key concentration gradient in the mitochondria?
A
The proton gradient.
26
Q
Two key take homes regarding mitchondrial diseases.
A
- Diseases which result from mitochondrial dysfunction tend to be heterogenous in their severity� (due to normal and mutant DNA being present within same individual or cell at different ratios).
- Diseases which result from mitochondrial dysfunction tend to be progressive– they get worse with age.�
27
What are the three functions of the tricarboxylic acid cycle (TCA cycle)?
1. Oxidize 2 carbons from acetate to CO2
2. Reduce NADH and FADH2, generate GTP
3. Generate precursors for biosynthesis
28
Give the pathology and cause of myoclonic epilepsy and ragged red fiber disease (MERRF).
Pathology: Myoclonic epilepsy, muscle tissue has ragged red fibers, progressive dementia.Cause: Point mutation in mtRNA(Lys)
29
Give the pathology and cause of Leigh disease (subacute necrotizing encephalopathy.
Pathology: Optic atrophy, opthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, and developmental.Cause: 7-20% of cases have mutations in Fo subunits of FoF1ATPase.
30
How is pyruvate dehydrogenase regulated?
By phosphorylation/dephosphorylation on E1 alpha subunit. PDH kinase phosphorylates E1, thus inactivating PDH. Activated by acetyl CoA and NADH. Inhibited by pyruvate and ADP.
PDH phosphatase phosphorylates E1 subunit. Activated by Ca++.
31
What links glycolysis to TCA cycle?
Pyruvate dehydrogenase (PDH). Defects in PDH can lead to serious neurological conditions.
32
What is the protein complex that transports pyruvate into the mitochondria?
Mitochondrial pyruvate carrier (MPC). Inherited point mutations in MPC1 cause lactic acidosis and hyperpyruvatemia.
33
If you shut off the TCA cycle, which two products build up and where do these products help out?
1. Malate. Used as a gluconeogenesis substrate.
| 2. Citrate. Used in fatty acid synthesis.
34
What catalyzes the oxidative decarboxylation from isocitrate to alpha-ketoglutarate and how is this regulated?
Isocitrate dehydrogenase (IDH). Regulated by the ratio of ADP to ATP in the mitochondria. ADP activates and NADH acts as allosteric inhibitor of IDH.
35
Why is the TCA cycle amphibolic?
Catabolic: Reduces NAD+ and FAD for the generation of ATP via the electron transport chain.
Anabolic: TCA intermediates are feedstock for other biosynthetic pathways.
36
Where does the TCA cycle happen?
In the mitochondrial matrix. Along with PDH. Glycolysis is in cytosol.
37
What are the substrates that leave the TCA cycle for other jobs, and what are those jobs?
1. Oxaloacetate: amino acid biosynthesis
2. Citrate: fatty acid biosynthesis
3. Malate: Gluconeogenesis
4. Alpha-ketoglutarate: glutamate to GABA
5. Odd chain fatty acids come in and contribute with succinyl CoA for heme biosynthesis.
38
What reaction increases the capacity of the TCA cycle after a high carb meal?
Pyruvate carboxylase converts pyruvate to oxaloacetate.
39
What is the key rate limiting enzyme in the TCA cycle?
Isocitrate dehydrogenase.
41
What are the reactions titled that replace TCA cycle intermediates that leave the cycle for other pathways?
Anaplerotic reactions.
42
During exercise, what reaction fills up amount of oxaloacetate?
Muscle contraction..AMP deaminase..Aspartate...fumarate to malate to oxaloacetate.
43
Define myoadenylate deaminase deficiency.
Inherited mutations in the gene coding the muscle specific AMPD1 isoform of AMP deaminase resulting in an inactive enzyme . Hallmark is exercise intolerance, can't increase capacity of TCA cycle. No increase in blood ammonia after exercising.
44
How many protons can go through ATP synthase? How many protons make one ATP?
12 protons. 4 protons make 1 ATP. Thus, one turn of the rotor generates three ATP.
45
Energy of the electron transport chain.
Negative delta G at each step. 34.75 kcal/mol of heat is generated.
46
Where does energy for transport come from?
1. Electrochemical gradient: Matrix side of membrane is negative compared to intermembrane side
2. pH gradient: concentration of H+ is lower in matrix than in intermembrane space.
47
Three types of transport systems.
1. Antiporters: charge gradient
2. Symporters: proton gradient and charge gradient
3. Uniporters: one direction; charge gradient
48
Describe coupling of the electron transport chain.
Electron transport is coupled to generation of ATP. If ATP synthase activity stops (high ratio of ATP/ADP), electron transport ceases. Or in case of hypoxia.
49
Describe uncoupling of the electron transport chain.
Uncoupling is when electrons are transferred from NADH to O2 without the generation of ATP. Three types:1. Adaptive thermogenesis: usually in infants; proton channel UCP12. Chemical uncoupling: toxin transport2. Mechanical uncoupling: damage to membrane
50
What is the inner mitochondrial membrane permeable to?
O2, NH3, CO2, & H2O
51
What are 2 chemical uncouplers?
-Dinitrophenol (DNP) (explosive)-Salicylate (product of aspirin)
52
What 2 drugs block complex I (NADH dehydrogenase)?
-Rotenone (pesticide)-Amytal (barbituate)
53
What drug blocks complex III (cytochrome b-c1 complex)?
Antimycin A (antibiotic)
54
What 3 drugs block complex IV (cytochrome c oxidase)?
-Cyanide (smoke, industrial chemical)-Carbon monoxide (combustion product)-Azide (antimicrobial agent, AZT)
55
What drug blocks complex V (ATP synthase)?
Oligomycin (antibiotic)
56
What drug blocks DNA pol-gamma (mitochondrial DNA replication enzyme)?
AZT (zidovudine) (anti-retroviral drug)
57
What are the two functions of the pyruvate/malate cycle in relation to lipogenesis?
1. Transports acetyl CoA from the mitochondria to the cytosol.
2. Malic enzyme generates NADPH to power fatty acid synthesis.
59
When are fatty acids made?
They are synthesized from acetyl CoA in liver cells whenever ingested calories exceed the requirement for energy.
60
How does citrate play into fatty acid synthesis?
In conditions of excess energy, isocitrate dehydrogenase is inhibited by a high NADH/NAD+ ratio. This drives citrate towards fatty acid synthesis (from the TCA cycle).
61
What pathway is an alternative to glycolysis?
The pentose-phosphate pathway.
62
What is the reaction sequence in Beta oxidation? In fatty acid synthesis?
Beta Oxidation
OHOB: Oxidation, Hydration, Oxidation, Bond Cleavage
FA synthesis Oppo: Bond formation, reduction, dehydration, reduction.
Differences: Beta oxidation occurs in mitochondria with multiple proteins. FA synthesis occurs in cytosolic compartment with one enzyme (fatty acid synthase)
63
Describe the two important sulfur atoms on fatty acid synthase.
1. From a phosphopantetheinyl group covalently linked to a serine residue on acyl carrier protein subunit of FAS.
2. From a cysteine side chain on another protein subunit of FAS.
64
Where does lipid synthesis take place?
Cytoplasm.
65
What is the rate limiting step in fatty acid synthesis?
Cytoplasmic acetyl CoA is converted to malonyl CoA by the addition of CO2. Acetyl CoA carboxylase catalyzes this reaction with biotin as a cofactor.
66
How is rate limiting step in fatty acid synthesis regulated?
Activated: Citrate (allosterically), insulin increases transcription, xylulose 5-phosphate (from pentose-phosphate pathway) increases transcription, insulin stimulates dephosphophorylationInhibited: Palmitoyl CoA allosterically (product), phosphorylation by AMPK, glucagon to cAMP to PKA to inhibitory phosphorylation
67
What is malonyl CoAs role in B-oxidation of FA?
By allosterically inhibiting carnitine palmitoyl transferase I (CPT-I), beta oxidation of newly synthesized fatty acids is prevented.
69
Where does the four carbon fatty acid chain get built and where does it transfer to on the fatty acid synthase?
Built on the phosphopantetheinyl and transferred to the cysteine.
70
When does fatty acid synthase stop the reaction?
When the acyl chain is 16 carbons long. This is palmitate.
71
How are triacylglycerols made?
1. 2 FA CoA get attached to glycerol 6-phosphate.
2. Phosphatidic acid takes of Pi from complex to make diacylglycerol.
3. FA CoA gets added on to make triacylglycerol
4. Triacylglylcerol is packaged in the Golgi to make blood VLDL or goes to adipose stores.
72
Describe how palmitate can be elongated.
Palmitoyl can be elongated two carbons at a time in the ER. Carbons courtesy of malonyl CoA.
73
How does the body unsaturated carbon carbon bonds?
Done by fatty acyl CoA desaturase. Latches on to acetyl CoA. Can only desaturate bonds that are at least 9 carbons away from omega end. Thus, omega 3 and omega 6 must be obtained from diet.
74
What are some common glycerophosphates?
```
phosphatidylcholine
phosphatidylethanolamine
phosphatidylserine
phosphatidylinositol
bisphosphate
```
75
What are the two most important dietary unsaturated FA?
Linoleic (18:2 9,12) and linolenic (18:3 9,12,15). Linolenic can be desaturated to arachidonic acid (can't be synthesized de novo since has carbon carbon bonds near omega end), which is a precursor of prostaglandins.
76
What is the backbone of triacylglycerol and where does it come from?
Glycerol 3-Phosphate. In liver, lipolysis of triacylglycerol produces glycerol, which can be phosphorylated by glycerol kinase to produce glycerol 3-phosphate. Glycerol 3-phosphate dehydrogenase is used to make glycerol 3-phosphate from dihydroxyacetone phosphate from glycolysis (adipocytes and liver).
77
What are the factors that allow fat to be stored in adipose tissue?
Need carb excess and storage only happens when glycolysis is around, unless in liver. Liver can store and make fatty acids at same time.
78
How are the fatty acids (not dietary) brought to the tissues and used?
Packaged by golgi into VLDL, which then float around blood. Lipoprotein lipase (LPL) is @ lumen of capillary endothelial cells. This cleaves off FA, allowing them to enter cells. In muscle cells they undergo beta oxidation, stored as triacylglycerols in adipocytes (req. glycolysis).Glycerol backbone recycled in liver to glycerol 3-phosphate.
79
What are glycerophospholipids mainly used for?
Cell membranes, but also constituents of lipoproteins, bile, and lung surfactant.
80
What is the basic structure of a phospholipid?
Glycerol backbone, 2 fatty acids attached along with a phosphate head group. Looks like triacylglycerol.
81
What is the difference between glycerophospholipids and sphingolipids?
Sphingolipids use ceramide instead of glycerol for their backbones. Ceramide derived from serine and palmitoyl CoA.
82
What is the most important sphingolipid?
Sphingophospholipid sphingomyelin, present in the myelin sheaths of nerve fibers.
83
What is the clinical significance of cerebrosides and gangliosides?
Lack of ability to break down A cerebroside and A ganglioside results in several fatal diseases.
84
Where does membrane synthesis occur?
Phosphoglycerides (phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine) are synthesized by the endoplasmic reticulum.
Sphingomyelin is made from sphingosine, which is synthesized by the Golgi apparatus
Glycolipids are also made from sphingosine, in the Golgi apparatus.�
85
What is the most abundant lung surfactant?
Dipalmitoylphosphatidylcholine. Sphingomyelin is another. Ratio of sphingomyelin:phosphatidylcholine in amniotic fluid is indicator of gestational progress. Late in the game much more phosphatidylcholine than sphingomyelin.
86
How is the ER involved in quality control of newly synthesized proteins?
An accumulation of misfolded proteins triggers:
- Heat-shock response
- Unfolded protein response
87
What are the 4 mechanisms to organize proteins in membranes?
1. Self-assembly into aggregates
2. Tethered to extracellular molecules
3. Tethered to intracellular molecules
4. Bind to proteins on adjacent cell
Asymmetric protein distribution is vital for tissue function.
88
What specific functions are associated with cholesterol?
- Stiffens membrane
- Reduces permeability
- Inhibits phase changes
89
In addition to triacylglycerol storage, what do adipocytes do?
Release peptide hormones leptin (when triacylglyceride levels are high, secretion increases) and adiponectin (decreases in obesity). Related to decreasing appetite.
92
What are the basic components and molecular architecture of eukaryotic membranes?
Lipid molecule and a protein molecule. Their basic architecture is that of a lipid bilayer with associated proteins.
93
What are the major types of membrane lipids?
-Phospholipids (4 major types: 3 based on glycerol, 1 based on sphingosphine)-Cholesterol: Stiffens membrane, reduces permeability, inhibits phase changes-Glycolipids: protection (glycocalyx), surface prop., cell ID, cell adhesion
94
What is the unfolded protein response?
- increased expression of ER chaperones to facilitate refolding
- increased expression of genes involved in retrotranslocation and proteasomal degradation
- Selective supression of further protein synthesis (genes involved in UPR continue to be expressed)
95
What is the structure and function of the Golgi apparatus?
Structure: a series of flattened cistern along with membranous tubules and vesicles.Function:
- Receives lipid and protein products from the ER
- Returns 'escaped' proteins that should be resident in ER
- Modifies glycoproteins (both trimming and addition)
- Sulfation and other post-translational modifications
- Glycolipid and sphingomyelin production
- Adds O-linked oligosaccharides to proteoglycans�
96
What are the 3 main routes out of the Golgi apparatus? How are they controlled?
- Lysosomes (signal mediated diversion: mannose 6-phosphate receptor)
- Secretory vesicles (signal, but not well understood)
- Plasma membrane (direct exocytosis in vesicles is default pathway if no other signal is present)
97
What are the prominent types of coat proteins involved in vesicular trafficking?
COPI-mediates intra-Golgi and Golgi to ER transport-Arf is the GTP-binding protein involved
-Escaped ER proteins in Golgi have KDEL AA sequence, which tags them for return
COPII -mediates ER to Golgi transport-Sar1 is the GTP-binding protein involved
Clathrin -endocytosis, Golgi to endosomes/lysosomes
98
What are the three sets of proteins that play critical roles in accurate delivery and fusion of vesicles? In addition to these three, what else is a critical ID in determining where vesicles form and fuse?
- Rabs (identifiers)
- Rab effectors (tethering protein)
- SNAREs (mediate fusion, v-SNARE and t-SNARE bind to bring membranes in close contact)
- lipid content of membranes, specifically phosphatidylinositol species
99
What are the 3 paths to lysosomes?
- autophagy
- phagocytosis (special form of endocytosis that involves engulfment of large particles)
- endocytosis (formation of lysosomes from Golgi and endosomes;pinocytosis and phagocytosis)
100
What are mitochondria?
Double-membraned organelles involved in:
- ATP production
- Ca++ regulation
- Apoptosis
101
How are nuclear-encoded cytosolic mitochondrial proteins recognized and imported into mitochondria?
TOM – Transporter of the outer mitochondrial membrane (one)
TIM – Transporters of the inner mitochondrial membrane (two TIMs have been discovered)
OXA – Transports proteins synthesized in the matrix outward
102
What are peroxisomes?
Single membrane bound organelles.
- oxidative reactions
- B-oxidation of fatty acids
- Formation of myelin phospholipids
103
How is the directionality (import vs export) of transport in the nucleus regulated?
Import: Bind import receptors in the presence of GDP, and dissociate in the presence of GTP
Export: Bind export receptors in the presence of GTP, and dissociate in the presence of GDP.
GTP is in nucleus, GDP is in cytoplasm.
104
What are the 3 major types of fibers present in the cytoskeleton?
- microfilaments (support/organize plasma membrane, shape, motility)
- microtubules (organize cytoplasm, cell division, cilia/flagellae motility)
- intermediate filaments (strengthen cytoplasm/tissues, support nucleus, epidermal appendages)
105
Define lipid rafts.
Specialized patches of lipids and proteins present in membranes. Rich in sphingolipids, cholesterol, and certain proteins. May be sorted to transport vesicles and involved with signal transduction.
106
What is the difference between integral membrane proteins and peripheral membrane proteins?
Integral membrane proteins require disruption of the bilayer structre to be released, whereas peripheral membrane proteins are more loosely associated with the membrane via protein-protein interactions.
107
What specific functions are associated with phosphatidylserine and phosphatidylinositol lipids?
Phosphatidyl serine has a net negative charge. If lots are on the external surface, signals for macrophages to engulf. Phosphatidyl inositol is often involved with cell signaling and membrane ID.
108
What is the glycocalyx?
"Sugar Husk". Covalently added sugar groups added to plasma membrane proteins on non-cytosolic side. Functions include protection, ID, and adhesion.
109
What are the functions of membrane lipids and proteins?
?
110
What is Paclitaxel.. taxol?
A drug that binds and stabilizes microtubules. Fatal to cell. Cancer drug because it stops cell division.
111
What is the endoplasmic reticulum (ER)?
An organelle where protein synthesis, lipid synthesis, Ca++ regulation, and detoxification takes place.
112
What are the functional differences between RER & SER?
RER has ribosomes on it, thus it is associated mainly with protein synthesis.SER is associated with lipid synthesis, Ca++ regulation, and detoxification.
113
What do actin and tubulin have in common?
-Both have a polarity-Both grow from plus end-Both regulated by nucleotides (Actin-ATP; Tubulin-GTP)
114
What's significant about intermediate filaments?
-Do NOT appear to have a polarity- Usually expressed in tissue specific manner
115
What IF proteins are expressed in the specific tissues?
-Keratins;epithelia-Vimentin-like Ifs; mesenchymal origin & glial cells-Neurofilament IFs; neurons-Lamins; all nucleated cells
116
What size molecules can fit thru nuclear pores?
< 5000 D freely permeable5000-50000 somewhat>50,000 D must be actively transported
117
What are some important proteins associated with actin (not all inclusive)?
-Motor proteins (type I and II myosin)-Capping proteins (actin capping protein)-Nucleation/polymerization proteins (WASP, ARP)-Signaling proteins (rho, rac, cdc42)
118
What are 2 major categories of microtuble-associated proteins (MAPs)?
-Structural MAPs-Motor MAPs (dyneins move things toward '-' end & kinesin moves things toward '+' end)
119
What is an example of IF-associated proteins?
Plectin -a high molecular weight protein involved in interlinking the IF cytoskeleton with other cytoskeletal elements
122
What is the function of the urea cycle in the fasted state?
To convert nitrogen to urea, which can be excreted in urine. If this didn't work, you have hyperammonaemia.
123
What are the sources of nitrogen for urea and how are they transported to the liver?
-deamination of amino acids-transamination of amino acids (aspartate)Transported by glutamine and alanine.
124
What are the key amino acids involved in protein digestion and amino acid turnover? What are their deamination products? What is their role?
1. Glutamate; alpha-ketoglutarate; the amino group pool of the cell2. Aspartate; oxaloacetate; donates nitrogen to the urea cycle3. Alanine; pyuvate; key role in gluconeogenesis (donates carbon skeleton)4. Glutamine; glutamate; transports nitrogen to liver for urea cycle
125
What are the three ways by which the urea cycle is regulated?
1. Available of substrates (main regulator)2. Allosteric regulation of carbomoyl phosphate synthetase I (CPS-I) and transcriptional regulation of urea cycle enzymes. This is done by a build up of arginine, which increases the synthesis of N-acetyl-glutamate (NAG), which allosterically activates CPS-I3. Buildup of arginine also increases arginase activity, which converts arginine to urea.
126
What three enzymes can fix free nitrogen?
1. Glutamate dehydrogenase2. Glutamine synthetase3. Carbamoyl phosphate
127
What is ornithine's role in urea cycle?
Ornithine plays an analagous role as oxaloacetate in TCA cycle in the fact that it carries and is regenerated.
128
Know the treatment plan for hyperammonaemia.
See screenshot.
129
What is HHH syndrome?
In hyperammonaemia, hyperornithaemia, homocitrullinaemia syndrome (HHH syndrome), the ornithine / citrulline antiporter is defective.
130
What are some treatments for inherited disorders of the urea cycle?
-Low protein diet-N carbamoylglutamic acid (allosteric activator of CPS I)-Eliminate nitrogen in alternative pathways (arginine, benzoic acid, phenyl butyrate)-liver transplant/hepatocyte transfusion-Viral transduced gene therapy
131
Define kwarshiorkor.
Anemia of protein deficiency.
132
Define hepatic encephalopathy.
Accumulation of nitrogenous products that has an adverse effect on the brain.
133
Know the enzymes and disorders that can occur without them.
Reference urea cycle picture.
134
What are the 5 enzymes of the urea cycle?
1. Carbamoyl phosphate synthetase I (CPSI)2. Ornithine transcarbamoylase3. Arginosuccinate synthetase4. Arginosuccinate lysase5. Arginase
137
What is the function of glycogenesis and fatty acid biosynthesis in the fed/absorptive state?
To store energy.
138
What is the function of glycogenolysis, gluconeogenesis/ fatty acid beta oxidation which predominate in the fasted/post-absorptive state?
To release energy.
139
How is insulin secreted from the beta cells of the pancreas?
K+ is pumped out of the cell. When carbs come into the cell through GLUT 2 transporter, they undergo glycolysis, TCA cycle, and the ETC. ATP results, which inhibits the K+ channel. This allows the voltage gated Ca++ channel to open, letting Ca++ in which binds to the vesicle holding insulin. This releases insulin into the blood.
140
How does insulin cause a decrease in blood glucose concentration?
The insulin receptor is a tyrosine kinase. Insulin activates phosphatases and inactivates kinases. Eventually, GLUT 4 transporters are increased on the membrane, bring in more glucose from blood.
141
Describe insulin maturation.
Preproinsulin to proinsulin to insulin. C peptide is cleaved when proinsulin becomes insulin . Insulin is combined with Zn++ to become a hexamer.
142
Describe glucagon maturation.
Proglucagon undergoes proteolytic processing to become glucagon.
143
How is glucagon released?
Insulin and glucose both prevent glucagon secretory vesicles from fusing with the plasma membrane and releasing glucagon. When these signals are low, it is released.
144
How does glucagon regulate pyruvate kinase?
When glucagon binds, it acts to phosphorylate pyruvate kinase, rendering it inactive.
147
What are the 3 key cofactors for enzymes in amino acid metabolism?
-PLP: Transaminations, deaminations, carbon chain transfers-FH4: One carbon transfers-BH4: Ring hydroxylations
148
What are the 9 essential amino acids?
M.V. Pitthall1. Methionine2. Valine3. Phenylalanine4. Isoleucine5. Tryptophan6. Threonine7. Histidine8. Arginine (essential during growth, not for adults)9. Leucine10. Lysine
149
What 3 ways can amino acids be derived and degrade into?
-Glycolysis intermediates-TCA cycle intermediates-Acetyl CoA & acetoacetate
150
What two amino acids are derived from glycolytic intermediates?
Alanine (transaminated from pyruvate) and Serine (from 3-phosphoglycerate). Serine can then be made into glycine and cysteine. Cysteine can then go to pyruvate.
151
What is cystinuria and how does it result?
Cystinuria results from inherited mutations (autosomal recessive) in the amino acid carrier for cysteine and basic amino acids (lysine, arginine and ornithine). SLC7A9 defect.Cysteine precipitates, forming kidney stones .
152
What is the major gluconeogenic amino acid?
Alanine. Transaminated by alanine aminotransferase (ALT) to pyruvate. ALT in blood is indicator of liver damage.
153
What amino acids are derived from TCA cycle intermediates?
From oxaloacetate:Aspartate (which can then form asparagine)From alpha-ketoglutarate:Glutamate (which can then form proline, arginine, and glutamine)All amino acids SYNTHESIZED by intermediates can be degraded back to TCA cycle intermediates.
154
What is one way glutamate can be produced from alpha-ketoglutarate?
Transamination by aspartate aminotransferase (AST). AST in blood also indicates liver damage.
155
What amino acids can be made into fumarate?
-Asparate-Tyrosine (also acetoacetate)-Phenylalanine (also acetoacetate)
156
What amino acids are associated with Maple Syrup Urine Disease (MSUD)?
High amounts of branched chain AA. Isoleucine, valine, and leucine.
157
What amino acids are associated with PKU, Tyrosinemia I&II, and alcaponuria?
Phenylalanine and tyrosine.
158
What is the cause and the symptoms of MSUD?
Autosomal recessive deficiency in branched chain alpha-keto acid dehydrogenase. Thus, you get a build up of valine, isoleucine, and leucine. Presents in 1 week old infants with convulsions, vomiting, maple syrup odor in urine.
159
What are the 3 different types of MSUD? How are they treated?
-Classic: fatal if untreated. Acute treatment hydration and transfusion. Long term: low BCAA diet.-Intermittant-Mild Intermittent and mild can be treated with very high doses of thiamine, a precursor to TPP.
160
Define phenylketonuria (PKU).
A defect in phenylalanine hydroxylase prevents tyrosine biosynthesis. Phenylalanine accumulates in the brain and blood. Tyrosine becomes an essential amino acid. Infants normal at birth, gradually develop seizures, cognitive delay, light complexion, and mousy odor.Defects in tetrahydrobiopterin metabolism e.g. dihydropteridine reductase can mimick PKU.Treat with low phenylalanine diet.
161
Define tyrosinemia (type II)
A rare autosomal recessive mutation of tyrosine aminotransferase. Serum tyrosine is elevated.Patients develop plaques on the hands and feet, corneal ulcers, and frequent mental retardation .
162
Define alcaptonuria.
A rare autosomal recessive deficiency in homogentisate oxidase.Homogentisate accumulates and is excreted in urine, giving it a dark color. Patients are asymptomatic until middle age, when they develop arthritis, back pain, renal calculi.Diagnosis: Ochronosis (dark spots of polymerized homogentisic acid in the sclera and ear cartilage)Homogentisic acid in urine.
163
Define tyrosinemia (Type I).
An inherited disorder of fumaryloacetoacetate hydrolase (FAH) results in accumulation of succinlyacetone.Presents as acute hepatic crisis, usually at 2-4 months of age: Jaundice (can’t make heme soluble enough to excrete in urine), hepatomegaly (can palpate liver and feel it being large), elevated AST & ALT, hypoglycemiaDiagnosis: Succinylacetone in urine and blood Treat with nitosinone.
164
What can low levels of isoleucine, leucine, and valine indicate?
A less common form of autism.
