Metabolism Sessions 1-6 Flashcards
(425 cards)
1
Q
Which is the natural stereoisomer form of a monosaccharide?
A
D
2
Q
How do carbohydrates exist?
A
As mono, di or polysaccharides
3
Q
In a typical western diet, how many grams make up the carb intake?
A
300
4
Q
What makes up 1% of wet weight in the body?
A
Carbohydrates
5
Q
How is the energy from carbohydrates stored in the body?
A
First ~300g as glycogen, nucleic acids, glycolipids and glycoproteins then as TAGs in adipose tissue
6
Q
At what level is glucose always present in the blood?
A
~5 mmol per litre
7
Q
What can excessive dietary intake of galactose, fructose and glucose lead to respectively in the blood?
A
Galactosaemia
Fructose intolerance
Diabetes mellitus
8
Q
What glucose level in the blood confers with diabetes?
A
> or equal to 7 mmol per litre
9
Q
What bond is found in disaccharides?
A
O-glycosidic
10
Q
What are the monomers of sucrose, lactose and maltose respectively?
A
Sucrose: glucose and fructose
Lactose: galactose and glucose
Maltose: 2x glucose
11
Q
Where does maltose come from in the diet?
A
Digestion product of dietary starch
12
Q
When is a disaccharide non-reducing?
A
If aldehyde and/or ketone groups of both monomers are involved in forming the glycosidic bond
13
Q
Give an example of a non-reducing disaccharide.
A
Sucrose
14
Q
What are mainly homopolymers?
A
Disaccharides
15
Q
What is the structure glycogen?
A
Glucose units linked by alpha 1-4 and alpha 1-6 bonds which give a highly branched structure
16
Q
Where is glycogen stored?
A
In granules in the liver and skeletal muscle
17
Q
What is the structure of starch?
A
Amylose with alpha 1-4 binds and amylopectin with alpha 1-4 and alpha 1-6 bonds
18
Q
What does hydrolysis of starch release in the GI tract?
A
Glucose and maltose
19
Q
Why can the human body not digest cellulose?
A
It does not have the enzymes needed to break beta 1-4 bonds present between glucose molecules
20
Q
If it can’t be digested, why do we need to eat cellulose?
A
Important for normal GI function
21
Q
Where is starch and glycogen digested to dextrins?
A
In the mouth by salivary amylase
22
Q
Where are dextrins digested to monosaccharides?
A
In the small intestine by pancreatic amylase
23
Q
What is attached to the brush border membrane of epithelial cells to aid digestion?
A
Pancreatic amylase, isomaltase, sucrose and lactose
24
Q
How does a low level of lactase cause diarrhoea?
A
Lactose remains in colon lumen and increase osmotic pressure to water moves into the lumen
25
How does a low level of lactose cause bloating?
Colonic bacteria digest the lactose present in the colonic lumen and produce hydrogen, carbon dioxide and methane
26
How are glucose, galactose and fructose absorbed into the blood?
Actively transported into absorbitive cells lining gut and then move by facilitated diffusion into blood and tissue
27
What does facilitated diffusion of glucose into the tissues require?
GLUT1-5
28
Which GLUT transporter is upregulated in response to high levels of insulin in skeletal muscle and adipose tissue?
4
29
Can all tissues remove glucose, galactose and fructose from the blood?
Yes
30
Where is the major site of fructose and galactose metabolism?
Liver
31
Roughly how much glucose is needed per day to supply the tissues who have an absolute need for glucose?
180 g
32
Which areas of the body have an absolute glucose requirement?
```
RBCs
WBCs
Kidney
Lens of eye
CNS
```
33
What is the central pathway of glucose metabolism which happens in all tissues?
Glycolysis
34
What are the functions of glycolysis?
Oxidise glucose
Produce NADH
Net synthesis of 2 ATP
Produce glycerol phosphate and 2,3-BPG
35
What are the main features of glycolysis?
Exergonic
Oxidative
No loss of carbon dioxide
Irreversible pathway
36
What is the purpose of converting glucose to G6P during glycolysis?
Makes it ionic so that it doesn't cross the membrane
Increases reactivity so can follow a different pathway
Allows formation of high phosphoryl-group transfer potential compounds
37
Why are steps 1 and 3 in the glycolytic pathway irreversible?
Have a very negative delta-G
38
Which step of the glycolytic pathway is the committing step to glycolysis?
3
39
What does the initial investment of energy in glycolysis do to glucose?
Makes it less stable so it is more easily catabolised
40
What occurs in the second phase of glycolysis?
C3 --> 2C3 which are interconvertible
Small amount of reducing power is captured
Substrate level phosphorylation allows for ATP synthesis
41
Which glucose metabolism pathway is cytosolic?
Glycolysis
42
Which glucose metabolism pathway is cytoplasmic?
Pentose Phosphate pathway
43
Where does the pentose phosphate pathway occur?
Liver
RBCs
Adipose tissue
44
What are the functions of the pentose phosphate pathway?
Produce NADPH for reducing power for anabolic processes
| Produce C5 sugar ribose for nucleotide synthesis
45
What is the NADPH generated in the pentose phosphate pathway used for?
Lipid synthesis in liver and adipose tissue
Maintain free -SH groups on cysteine residues in RBCs
Detoxification
46
What are the features of the pentose phosphate pathway?
High activity in dividing tissues
Carbon dioxide produced so irreversible
Considered in two phases
47
What happens in the first phase of the pentose phosphate pathway?
G6P makes C5 sugar phosphate, NADPH, hydrogen ions and carbon dioxide
48
Which enzymes are involved in the first phase of the pentose phosphate pathway?
Glucose-6-phosphate dehydrogenase
| 6-phosphogluconate dehydrogenase
49
What happens in the second phase of the pentose phosphate pathway?
Complex series of reactions to convert unused C5 sugar phosphates to glycolysis intermediates
50
How is the second phase of the pentose phosphate pathway regulated?
Controlling activity of G6PD with NADP+ which activates it and NADPH which inhibits it
51
What are the products of the second phase of glycolysis?
ATP
1,3-BPG
Phosphoenolpyruvic acid
52
What is glycerol phosphate needed for?
TAG synthesis in liver and adipose tissue
53
What is glycerol phosphate produced from in adipose tissue?
Dihydroxyacteone phosphate
54
Why is TAG synthesis not as dependent on rate of glycolysis in the liver as it is in adipose tissue?
Liver has glycerol kinase which it can use to phosphorylase glycerol
55
What is 2-3 BPG produced from in RBCs?
1,3-bisphosphoglycerate
56
What is 2,3-BPG?
An important oxygen affinity regulator
57
What does muscle tissue possess that enables the high energy of hydrolysis phosphate bond in ADP to drive ATP synthesis in an emergency?
Myokinase
58
How is glycolysis regulated by ATP levels?
Inhibited when high
| Stimulated when low
59
Why do most of the metabolic reactions in glucose metabolism not need to be regulated?
They are close to equilibrium
60
How can phosphofructokinase be regulated?
Inhibited by high ATP levels or glucagon
| Stimulated by high AMP or insulin
61
What are the products of anaerobic glycolysis?
Lactate
ATP
Water
62
What normally produces ~50 g of lactate per day?
```
RBCs
Skin
Brain
Skeletal muscle
GI tract
```
63
How is lactate dealt with once it has been released into the circulation?
Converted to glucose in liver and kidney
| Converted back to pyruvate and oxidised to carbon dioxide in heart muscle
64
How does lactic acidosis occur?
If plasma lactate concentration >5 mmol per litre it exceeds renal threshold and affects buffers
65
What can cause lactic acidosis?
```
Compromised circulation
Lack of thiamine
Shock
Strenuous exercise
Liver disease
Hearty eating
```
66
What appears in the urine in lactic acidosis?
Lactate
67
How is galactose liberated?
Digestion of lactose
68
Where is galactose metabolised?
Mainly liver but also kidney and GI tract by soluble enzymes
69
What are the products of galactose metabolism?
G6P and ADP
70
What does epimerase do?
UDP-glucose UDP-galactose
71
Why is it important for the epimerase reaction to be reversible?
So galactose can be formed during lactation
| So galactose can form UDP-glucose in glycogen synthesis
72
Which two enzymes can patients with galactosaemia lack?
Kinase or transferase
73
Which is the more common enzyme deficiency in galactosaemia?
Transferase
74
What accumulates in the tissues of patients lacking kinase enzyme in galactosaemia?
Galactose
75
What accumulates in the tissues of patients lacking the transferase enzyme in galactosaemia?
Galactose and galactose-1-phosphate
76
What happens to the accumulated metabolites in transferase deficient galactosaemia?
Reduced by aldose reductase to galacitol which depletes NADPH
77
What are the consequences of NADPH reduction in transferase deficient galactosaemia?
Raised intraocular pressure --> blindness
Non-enzymatic glycosylation of lens proteins --> cataracts
Inappropriate disulphide bond formation --> cataracts
78
Why are the liver, kidney and brain damaged in transferase deficient galactosaemia?
Pi sequestered so not available for ATP synthesis
79
Why does galactose spill into pathways it is not normal seen in during galactosaemia?
High Km values
80
Why does treating galactosaemia patients with a galactose free diet not cause a galactose deficiency?
UDP-glucose is present and this can be converted by epimerase
81
How is fructose produced in the body?
Hydrolysis of sucrose and ingestion of fruit
82
How is fructose metabolised?
Soluble enzymes in the liver catalyse its conversion to glyceraldehyde 3-phosphate, an intermediate of glycolysis
83
What causes G6PD deficiency?
Point mutation causing an X-linked gene defect
84
Which populations is G6PD more prevalent in?
Mediterranean
| Black USA males
85
What are the consequences of G6PD deficiency?
Insufficient NADPH levels
Inappropriate disulphide bridges form
Haemoglobin and other proteins become X-linked
86
What are Heinz bodies?
Insoluble aggregates of X-linked proteins in RBCs which cause haemolysis
87
What can cause acute haemolytic episodes in G6PD deficiency?
NADPH level reducing chemicals e.g. antimalarials, sulphonamides, glycosides
88
What happens to pyruvate before it can enter the TCA cycle?
Converted to acetyl CoA by pyruvate dehydrogenase
89
Why is pyruvate metabolism sensitive to vitamin B deficiency?
4 B vitamins are needed as cofactors for pyruvate dehydrogenase
90
Why is the PDH reaction irreversible?
Carbon dioxide is lost
91
What controls the PDH reaction?
PDH allosterically activated by ADP
| PDH allosterically inhibited by acetyl-CoA, ATP and NADH
92
What does the allosteric inhibition of PDH by acetyl CoA allow?
Acetyl-CoA from beta-oxidation to be used instead of that from glycolysis under certain conditions
93
How does insulin activate PDH?
Promotes dephosphorylation
94
Where does the conversion of pyruvate to acetyl CoA take place?
Mitochondrial matrix after transportation of pyruvate from the cytoplasm
95
What does PDH deficiency lead to?
Lactic acidosis
96
Why is the TCA cycle unidirectional?
Conversion of removed acetyl to carbon dioxide which is lost
97
Why does the TCA cycle require NAD+ and FAD?
It is oxidative
98
Where does the TCA cycle take place?
Mitochondrial matrix
99
How does the TCA cycle produce energy?
ATP/GTP
| Precursors for biosynthesis
100
What are the products of one molecule of glucose entering the TCA cycle?
6 NADH
2 FAD2H
2 GTP
101
Which molecules does the TCA cycle produce precursors of biosynthesis for?
Fatty acids
Amino acids
Haem
Glucose
102
How is the TCA cycle regulated?
Isocitrate dehydrogenase is allosterically activated by ADP and allosterically inhibited by NADH
103
Which enzyme in the catabolism of glucose must gluconeogenesis bypass?
PDH
104
What is the TCA cycle the central pathway of metabolism for?
```
Sugars
Fatty acids
Ketone bodies
Amino acids
Alcohol
```
105
How do the intermediates of the TCA cycle act?
Catalytically - no net synthesis or degradation
106
Why are there no known genetic defects to the TCA cycle?
They would be lethal
107
How many molecules of ATP are produced per molecule of glucose in that has entered the TCA cycle?
32
108
Where does oxidative phosphorylation take place?
Inner membrane of the mitochondria
109
Why is oxygen required in oxidative phosphorylation?
Final electron acceptor
110
What happens to NADH and FAD2H in oxidative phosphorylation?
Re-oxidised
111
How is energy used in oxidative phosphorylation?
30% to move H+ across membrane
112
Why are humans warm blooded?
70% of the energy in oxidative phosphorylation is dissipated as heat
113
What creates the proton motive force in oxidative phosphorylation?
Anions left on inside of inner membrane create [H+] gradient
114
Why does ATP synthesis occur in oxidative phosphorylation?
Return of proteins is energetically favoured electrically and chemically but can only happen via ATP synthase
115
How is discharge of the proton gradient prevented?
Impermeable membrane
116
How much ATP is generated by oxidation of 2 moles of NADH?
5 moles
117
How much ATP is generated by oxidation of 2 moles of FAD2H?
3 moles
118
How does the transfer of electrons differ between FAD2H and NADH?
FAD2H is lower energy so transfers electrons at a lower energy complex
119
How is oxidative phosphorylation regulated?
High ATP means no substrate for ATP synthase --> inward H+ flow stops, proton gradient rises and feedback inhibition takes place so e- transport is stopped
120
How are oxidative phosphorylation and electron transport usually regulated?
By mitochondrial [ATP] as they are tightly coupled
121
How do cyanide ions and carbon monoxide interfere with the electron transport chain?
Bind to cytochrome oxidase and prevent transfer of e- to oxygen therefore the pmf is not established
122
What does cytochrome oxidase contain which allows it to be used in electron transport?
Haem group that can change oxidation state
123
What percentage of BMR can be attributed to proton leak?
~20-25%
124
How do uncouples work?
Increase permeability of the IMM to protons so the gradient is dissipated and there is no pmf for ATP synthesis
125
Why are overweight people warmer than lean individuals?
Fatty acids act as uncouplers so more energy is dissipated as heat due to leaky IMM
126
What are dinitrophenol and dinitrocresol examples of?
Uncouplers
127
What genetic defects can reduce electron transport and ATP synthesis?
PTCs and ATP synthase encoded by mtDNA
128
What affects the efficiency of energy transfer and can be varied in some tissues?
Tightness of oxidative phosphorylation and electron transport coupling
129
Where is brown adipose tissue found in newborns?
Around vital organs
130
What does brown adipose tissue contain that allows uncoupling of oxidative phosphorylation from electron transport?
Thermogenin (UCP1)
131
How does thermogenin in brown adipose tissue cause an independent in temperature?
NA stimulates lipase --> FA from TAGs oxidised --> UCP1 activated which transports H+ back to mitochondria causing energy of pmf to be released as heat
132
How do the proteins in oxidative phosphorylation compare to those in substrate level phosphorylation?
OP: membrane associated complexes
SLP: soluble enzymes in cytoplasm and mitochondrial matrix
133
How does energy coupling in oxidative phosphorylation compare to substrate level phosphorylation?
OP: indirectly through generation and utilisation of pmf
SLP: directly through formation of high energy of hydrolysis bonds
134
How does the ability of substrate level phosphorylation and oxidative phosphorylation compare?
OP: cannot occur in oxygen absence
SLP: occurs to limited extent in oxygen absence
135
Which is the major process for ATP synthesis in cells needing lots of energy?
Oxidative phosphorylation
136
Why do carbohydrates require less oxygen than fatty acids to be metabolised?
They are already partially oxidised
137
Why are lipids more reduced that carbohydrates?
They have less oxygen and more hydrogen atoms per carbon atom
138
What are the four fatty acid derivatives?
FA
TAGs
Phospholipids
Eicosanoids
139
What is the function of eicosanoids?
Transmitter b/w neighbours
140
What are the 4 derivatives of hydroxy-methyl–glutamic acid?
Ketone bodies
Cholesterol
Cholesterol esters
Bile acids and salts
141
What are cholesterol esters used for?
Cholesterol storage
142
Which hydroxy-methyl-glutamic acid derivative is used in lipid digestion?
Bile acids and salts
143
What does vitamin A deficiency cause?
Scaly skin
144
What does vitamin E deficiency cause?
Muscular dystrophy
145
What does vitamin K deficiency cause?
Haemorrhaging anaemic babies
146
What are TAGs?
Hydrophobic molecules stored in anhydrous form in fatty globules in adipose tissue until there is an increase in metabolic load
147
What stimulates reduced TAG storage?
```
Glucagon
Adrenaline
Cortisol
Growth hormone
Thyroxine
```
148
What happens to the glycerol part of TAGs?
Hydrolysed in GI tract from TAG --> enters blood --> taken up by liver
149
What happens to the fatty acid part of TAGs?
Hydrolysed from TAG in GI tract --> carried by chylomicrons in blood --> taken up by adipose tissues
150
What are chylomicrons in the blood recognised by?
Tissues that need triglycerides
151
What is released by adipose tissue into the blood that can be taken up by muscles to provide energy?
Fatty acids
152
What are fatty acids carried by in the blood?
Plasma proteins e.g. Albumin
153
What happens to TAGs in the small intestine?
Hydrolysed by pancreatic lipase to release glycerol and FA using bile salts and colipase
154
What is colipase?
Protein factor
155
What happens to glycerol in the liver?
Turned into glycerol phosphate which can be used in glycolysis or TAG synthesis
156
What is the difference between saturated and unsaturated fatty acids?
Saturated: all single carbon bonds
Unsaturated: one or more double carbon bonds
157
Why are certain polyunsaturated fatty acids essential?
Mammals cannot introduce double carbon bonds beyond C9
158
What happens with lipolysis in stress response?
FA released and non-covalently bound to albumin and carried in blood to liver, heart and skeletal muscle for beta-oxidation
Glycerol is released into blood where it travels to the liver to be oxidised/converted to glucose/TAGs
159
Where does FA oxidation take place?
Cytoplasm
160
What is the function of fatty acyl CoA synthase?
Link FA to CoA by forming a high energy sulphide bond using ATP
161
Why do activated FAs not readily cross the IMM?
Hydrophobic acids w/a hydrophobic cofactor
162
How is the rate of FA oxidation controlled?
Need for cartinine shuttle to transport fatty-aceyl CoA across the IMM
163
What happens in the transport of fatty acetyl-CoA across the IMM?
Molecule modified into cartinine derivative which is recognised by the transporter --> into matrix where enzyme converts back to acetyl CoA so it is in its metabolic form
164
What prevents newly synthesised FA from being immediately oxidised?
Inhibition of fatty acyl-CoA transport by FA synthesis intermediate malonyl CoA
165
How do defects in the fatty acyl-CoA transport system present?
Poor exercise tolerance
| Increase in fat droplets in muscle cells
166
What is acetyl CoA a catoabolism product of?
FA
Sugars
Alcohol
Amino acids
167
Why is beta-oxidation of a fatty acid said to be a spiral cycle?
Gets shorter w/each turn until there is only one C2 unit left
168
Why can beta-oxidation not occur in the absence of oxygen?
Requires mitochondrial NAD+ and FAD
169
Is there any direct ATP synthesis in beta-oxidation of FA?
Nope
170
What happens to all intermediates and carbon atoms in beta-oxidation of FA?
Intermediates linked to CoA
| Carbon atoms converted to acetyl-CoA
171
Is more energy derived from FA oxidation or glucose oxidation?
FA oxidation
172
What can be said about the substrate and product in beta-oxidation of FA?
Both activated
173
Which ketone bodies are synthesised in the liver from acetyl CoA?
Acetoacetate
| Beta-hydroxybutyrate
174
How is acetone formed?
Spontaneous, non-enzymatic decarboxylation of acetoacetate
175
Why are ketone bodies present in plasma and excreted in urine?
Soluble in water
176
What occurs if ketone bodies are present in the blood above renal threshold?
Ketonuria
177
At what concentration is the plasma lactate level kept son start at?
178
Why level of ketone bodies is usually seen in the blood?
179
What is physiological ketosis?
Ketone bodies at 2-10 mM in the blood, seen in starvation
180
Why is pathological ketosis?
Ketone bodies at >10mM in blood seen in untreated type I diabetics with pear-drop smelling breath
181
What happens in the fed state to HMG-CoA which has been formed from acetyl CoA?
Goes to form cholesterol to increase the insulin/glucagon ratio
182
What happens in the starvation state to HMG-CoA?
Forms ketone bodies to decrease the insulin/glucagon ratio
183
How do statins work to lower cholesterol?
Inhibit HMG-CoA reductase to prevent conversion of HMG-CoA to mexalonate and then cholesterol
184
How are ketone bodies synthesised?
Acetyl CoA --> synthase --> HMG-CoA --> lyase ---> acetoacetate --> beta-hydroxybutyrate
185
How is ketone body synthesis controlled?
Isocitrate dehydrogenase which uses feed forward allosteric inhibition
186
What is required for ketone body synthesis?
FA for oxidation in liver after excess lipolysis in adipose
187
How can ketone bodies be used as a source of energy?
All tissues w/mitochondria (incl. CNS) convert to acetyl-CoA at a rate proportional to plasma concentration
188
How is acetone transported around the body?
In blood as it is soluble
189
What can beta-hydroxybutyrate carry?
Hydrogen
190
Why are ketone bodies used in starvation/diabetes?
Prime aim is to spare glucose for brain
191
What processes can spare glucose?
Glycogenolysis
Gluconeogenesis
Ketogenesis
Lipolysis
192
Why does the body preferentially break down muscle in starvation?
It does not want to lose tissue mass
193
What are the 4 basic stages of catabolism?
1: breakdown to building block molecules
2: breakdown to metaboli intermediates, release of reducing power and energy
3: TCA cycle, release energy and reducing power
4: conversion of reducing power to ATP
194
What energy stores make up the textbook 70 kg man?
~15 kg TAGs
~0.4 kg glycogen
~6 kg muscle protein
195
How do the typical energy stores change in obesity?
Glycogen and muscle protein masses stay the same but mass of TAGs greatly increases
196
How long after a meal does glycogenolysis occurs?
2 hrs
197
How long after a meal does gluconeogenesis occur?
8-12 hours
198
Why doe glycogen have a minimal osmotic effect?
It's structure
199
What forms the straight chain alpha 1-4 bonds in glycogen?
Glycogen synthase
200
What forms the branching alpha 1-6 bonds in glycogen?
Branching enzyme
201
What ratio are the alpha 1-4 and 1-6 bonds present in?
10:1
202
Why is the amount of glycogen stored in liver and skeletal muscle limited?
High polarity attracts a lot of water
203
What can glycogen storage diseases cause?
Tissue damage w/excessive storage
Fasting hypoglycaemia
Poor exercise tolerance
Abnormal storage affecting liver and/or muscle
204
Why is glycogen never completely degraded?
Small amount needed as primer
205
What can the body not do in von Gierke's disease?
Breakdown glycogen
206
How is glycogen synthesised?
Glucose + ATP --> G6P --> G1P + UTP + water --> UDP-glucose --> add on to existing glycogen
207
Which enzymes are needed for synthesis of glycogen?
Hexokinase/glucokinase
Phosphoglucomutase
Glycogen synthase/branching enzyme
208
What inhibits glycogen synthesis?
Phosphorylation by glucagon or adrenaline
209
What activates glycogen synthesis?
Dephosphorylation by insulin
210
How is glycogenolysis controlled with respect to glycogen synthesis?
Reciprocally
211
Which is the rate limiting step of glycogenolysis?
Conversion of glycogen to G1P by glycogen phosphorylase/de-branching enzyme
212
Which enzyme converts G1P to G6P?
Phosphoglucomutase
213
What is found only in the liver which can convert G6P from glycogenolysis into glucose?
Glucose-6-phosphatase
214
What precursors are used mainly in the liver but also the kidney cortex for gluconeogenesis after 8 hours of fasting?
Non-carbohydrate
215
Which enzyme controls the rate limiting step in galactose metabolism?
Fructose-1,6-bisphosphosphatase
216
Which enzyme is used for galactose, fructose and glycerol in gluconeogenesis?
PEPCK
217
How do the stimulators of gluconeogenesis act on the enzymes involved?
Increase expression and activity
218
When can the energy from TAG storage in adipose be mobilised?
~20 mins of aerobic exercise
Stress
Starvation
Second half of gestation
219
Why can FA not move through the blood-brain barrier to the CNS?
Endothelial cells in BV have very tight junctions
220
What is acetyl CoA converted into using ATP and NADPH in the cytoplasm of liver cells?
Fatty acids
221
How is acetyl-CoA transported out of the mitochondria if it is too big to pass through as it is?
Combines w/oxaloacetate to form citrate which can be transported, then reforms in cytoplasm
222
How are FA synthesised once acetyl-CoA has been transported into the cytoplasm?
Acetyl-CoA converted to malonyl-CoA
| Fatty acid synthase adds one C2 unit to growing FA per cycle
223
What is the growing fatty acid linked to in FA synthesis?
Acyl carrier protein (ACP)
224
Which enzyme controls the important regulatory step in FA synthesis?
Acetyl carboxylase
225
How is acetyl carboxylase controlled?
Citrate and insulin activate
AMP, glucagon and adrenaline inhibit
(Hormones cause covalent modification)
226
Are fatty acid oxidation and synthesis reversals of each other?
Nope
227
Why is the catabolism and anabolism of the same substrate usually not just a reversal of the same process?
Allows greater flexibility, better control and thermodynamically irreversible steps can be bypassed
228
What is special about lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, methionine and under certain conditions histidine, arginine, tyrosine and cysteine?
They are essential
229
What are amino acids used in the synthesis of?
```
Proteins
Purines
Pyrimidines
Porphyrins
Creatine
Neurotransmitters
Hormones
```
230
When is the nitrogen balance negative?
During starvation
231
When is the nitrogen balance positive?
During growth
232
What release free amino acids by breaking peptide bonds?
Proteases
| Peptidase said
233
What stimulates uptake of amino acids into skeletal muscle, adipose, and the liver as well as stimulating protein synthesis?
Insulin
| Growth hormone
234
Which hormone stimulates proteolysis and can be raised by steroid drugs?
Cortisol
235
What happens to amino acids once they've been released from the polypeptide?
Amino group is removed and carbon skeleton enters TCA cycle
236
What types of carbon skeleton can be left when the amino group is removed from a free amino acid?
Glucogenic
| Ketongenic
237
How do Ketongenic amino acids enter the TCA cycle?
Produce acetyl CoA which goes on to make ketone bodies
238
How do goucogenic amino acids enter the TCA cycle?
Produce pyruvate, oxaloacetate, fumarate, alpha-ketoglutarate or succinate to undergo gluconeogenesis
239
What is special about the catabolism of isoleucine, threonine, phenylalanine, tyrosine and tryptophan?
They can take either goucogenic or ketongenic pathways
240
What two ways can be used to transform excess amino acids metabolised in the liver into a less toxic form?
Transamination
| Deamination
241
Which enzymes are used in transamination what can be used to measure liver function?
ALT
| AST
242
Why does transamination disrupt energy supply?
It reduces TCA cycle activity
243
What does ALT convert?
Alanine to glutamate
244
What does AST convert?
Glutamate to aspartate
245
What stimulates transaminase in the liver?
Cortisol
246
What happens to the amine group removed from amino acids at physiological pH?
Converted to very toxic and soluble ammonium ion
247
Who can toxic ammonium ions be removed?
Via urea or glutamine
248
What is required to form glutamine in order to remove toxic ammonium ions?
Glutamate
Ammonia
ATP
249
Which enzyme is needed for glutamine synthesis?
Glutamine synthetase
250
How is excess glutamine dealt with?
Released from cells into blood where it travels to the kidneys to enter urine and the liver to form urea
251
Why is urea a good way to get rid of ammonium ions?
High N content
Non-toxic
V. water soluble
Chemically inert in humans
252
What nitrogen containing compound can bacteria in the gut break down?
Urea
253
What are the products of the urea cycle?
```
Urea
Fumarate
ADP
AMP
Pi
```
254
How may enzymes are there in the urea cycle?
5
255
Why is the urea cycle not regulated by feedback inhibition?
Function is disposal so controlled by protein intake
256
Where does the urea cycle take place?
Ornithine part in mitochondrial matrix and rest in cytosol
257
What is the result of a complete loss of any one enzyme in the urea cycle?
Death
258
Why does partial loss of an enzyme in the urea cycle cause vomiting, lethargy, irritability, mental retardation, seizures and coma?
Causes hyperanaemia which increases intermediates that interfere with the TCA cycle
259
How is a deficiency of an enzyme in the urea cycle treated?
Low protein diet and replacing amino acids w/keto acids
260
How is phenylketonuria detected?
Excess phenylketones excreted in urine and high levels in the blood
261
What causes phenylketonuria?
Autosomal recessive defect of gene on chromosome 12 which causes lack of phenylalanine hydroxylase enzyme
262
How is phenylketonuria treated?
Low phenylalanine diet
263
Why is mental retardation seen in PKU?
Tyrosine is not formed which is needed to synthesise noradrenaline, adrenaline and dopamine for CNS development
264
What causes homocystinuria?
Autosomal recessive defect on chromosome 21 causes complete deletion or reduced activity of cystathionine beta-synthase
265
What is made instead of cystathionine in homocystinuria?
Methionine
266
What does homocystinuria affect in the body?
Fibrillin-1 protein structure so tissue, muscle, CNS and CVS affected
267
Symptoms of which other disease involving chromosome 21 are linked with homocystinuria?
Down's syndrome
268
What other disease presents similarly to homocystinuria and can be confused on diagnosis?
Marian's
269
How do the relative toxicities of methionine and homocysteine compare?
Methionine is harmful at high levels but less so than homocysteine
270
What does cystathionine-beta-synthase need to function?
Active vitamin B
271
What treatment is given in homocystinuria where there is reduced activity of CBS?
Vitamin B supplement
272
Which important gas signalling molecule is linked with arginine?
Nitric oxide
273
What functions does nitric oxide have?
Vasodilator - maintenance of B.P.
Neurotransmitter
Inflammatory mediator
Memory storage
274
Which important gas signalling molecule is cysteine associated with?
Hydrogen sulphide
275
What is the function of hydrogen sulphide?
Vasodilator
Neuromodulator
Cytoprotective agent against oxidation (it's a reducing agent)
276
What is creatinine?
Breakdown product of creatine and creatine phosphatase in muscle cells
277
How does the release of creatinine vary?
Constant unless muscle is wasting when it becomes elevated
278
What is the importance of creatinine excretion over 24 hrs by the kidneys being proportional to muscle mass ?
Means urine concentration is a stable marker of urine dilution, blood concentration and measure kidney function
279
When is the level of urinary creatinine excretion over 24 hrs not proportional to the muscle mass of an individual?
If they are a carnivore or are wasting
280
What are the five classes of lipids?
```
Phospholipids
Cholesterol esters
Cholesterol
Fatty acids
Triacyglycerols
```
281
What is cholesterol he precursor to?
Steroid hormones and bile acids
282
What is the function of bile acids?
Emulsify fats in the GI tract
283
Where does cholesterol come from?
Some from the diet but mainly synthesised in the liver
284
How can a fatty acid be used to eliminate the polar part of a cholesterol molecule?
The OH on the cholesterol can be esterified with a FA
285
What is the most abundant protein in the blood?
Albumin
286
What does albumin carry?
~2% of lipids, mainly FA
287
What is the problem with using albumin as transport for lipids?
It has a limited capacity of ~3 mmol per litre so becomes saturated if lipid levels are too high
288
How is ~98% of lipid carried in the blood?
As lipoprotein particles
289
What is a lipoprotein?
Particle mainly constructed in the liver consisting of a TAG and cholesterol hydrophobic core surrounded by a protein, phospholipid and cholesterol coat
290
What is the function of the protein component of an apolipoprotein?
Stabilisation during transit
291
What is the role of phospholipids and cholesterol in the apolipoprotein?
Structural integrity
292
What is an apoprotein?
Specialised protein for lipid transport
293
How do different types of lipoproteins vary?
```
Size (5-100 nm)
Lipid and protein composition (2-55% protein)
Density
Surface charge
Function
```
294
How can lipoproteins be separated?
Electrophoresis or ultracentrifugation
295
What does each class of lipoprotein particle have?
Own set of specific apolipoproteins
296
What are the two general functions of apolipoproteins?
Activate enzymes
| Recognise CSM receptors
297
Where can ApoA (I) be found and what is its function here?
Intestine
| Structural HDL component
298
Where is ApoB100 found and what is its function?
Liver
| VLDL
299
Where can ApoC be found and what is its function?
Liver
| Cofactor activator of lipoprotein lipase/inhibits LPL
300
Where is ApoD found and what is its function?
Brain and testes
| HDL
301
Where is ApoE found and what is its function?
Liver, binding to LDL receptors
302
What is the function of ApoH?
Inhibits coagulation factors
303
What happens if there are polymorphisms in LDL receptors?
Early onset CVD
304
Order the classes of chylomicrons in increasing density.
VLDL
LDL
HDL
305
What are chylomicrons?
Recombined TAGs and apoprotein
306
What forms chylomicrons?
Enterocytes - simple columnar cells w/glycocalyx found on the intestinal lining
307
What is the function of chylomicrons?
Combine dietary TAGs split by pancreatic lipase and reformed w/apoprotein so to carry lipids form the diet to tissues
308
How long are chylomicrons usually present for in the blood following a meal?
4-6 hours
309
Where are VLDLs formed?
In liver for energy store
310
What are VLDLs rich in?
TAGs
311
What is the function of VLDLs?
Combine TAGs synthesised in the liver w/specific apoproteins to carry lipids from liver to tissues
312
Which is more important, the absolute LDL and HDL levels or the ratio between them?
Ratio
313
Where are LDLs formed?
In the liver
314
What are LDLs rich in?
Cholesterol
315
What is the function of LDLs?
Combine liver cholesterol w/specific apoproteins (esp. apoB100) to carry it to the tissues
316
What is the structure of an LDL?
Phospholipid she'll w/lots of cholesterol, filled w/cholesterol esters
317
What are high levels of LDLs associated with?
High risk of atherosclerosis
318
Where are HDLs formed?
Tissues
319
What is the function of HDLs?
Combine excess cholesterol in the tissues w/specific apoproteins to carry it to the liver so it cannot cause damage by being in the blood
320
What enzyme do endothelial cells have on their outside?
Lipase
321
What catches cholesterol and binds it?
Chylomicrons and VLDL
322
What happens to VLDL remnants?
Removed by liver or converted to other lipoprotein particles
323
What is necessary for recognition of cholesterol from LDL?
ApoB100
324
What controls ApoB100 receptor expression in the cell?
[cholesterol]
325
What happens when the LDL complex binds to the receptor on a cell?
Receptor/LDL complex taken in by endocytosis --> cholesterol ester is released and cleaved into cholesterol and FA
326
How are HDL particles loaded?
Nascent HDL shells made in the liver and VLDL tenants sequester cholesterol from capillaries which then mature into HDL particles
327
What is hyperlipoproteinaemia?
Raised levels of one or more lipoprotein classes
328
What causes hyperlipoproteinaemia?
Problems w/receptors, lipase enzymes or ApoE (for example) which results in over production or under removal
329
What lifestyle alterations can be sufficient to treat hyperlipoproteinaemia?
Reduce cholesterol and saturated lipid intake
Increase exercise
Stop smoking
330
What drugs can be used to treat hyperlipoproteinaemia?
Statins
331
What effects do statins have?
Inhibit HMG CoA reductase
Increase LDL receptor expression in hepatocytes
Increase vascular lipase secretion
Possible anti-inflammatory action
332
What effects does hypercholesterolaemia have around the body?
Cholesterol deposited on eyelids (xanthelasma), on tendons, corneal arcus
333
What is the pathogenesis of atherosclerosis?
Oxidised LDL in intima --> macrophages become foam cells --> accumulation in intima of BV walls --> fatty streak --> atheroma
334
What are foam cells?
Fat filled macrophages
335
What is an early warning sign of atherosclerosis?
Angina
336
What happens if an atherosclerotic plaque ruptures?
Clotting cascade is initiated and thrombus forms
337
Why do statins have a wide spectrum of side effects?
Pathway they act on is wide branching
338
Give an example of a useful species produced by the cholesterol pathway.
Coenzyme Q10
339
Why are statins taken before bed?
Most cholesterol is produced in the liver at night
340
Are statins universally effective?
No, varies from patient to patient so trial and error for treatment plan
341
What is the problem with statins and risk of CVD?
Statins save lives at high risk of CVD but controversy over whether to prescribe routinely for >10% risk
342
What is a dangerous byproduct of ATP production?
Reactive oxygen species
343
How are reactive oxygen species formed surfing ATP synthesis?
Electrons drop out of the electron transport chain and combine with oxygen
344
What do superoxide radicals damage?
DNA and CSM
345
How does superoxide dismutase (SOD) act as a defence mechanism against superoxide radicals?
Converts them to hydrogen peroxide which catalase can then turn into oxygen and water
346
Where is catalase found?
Widely distributed in cells
347
What ROS is produced by ionising radiation?
Hydroxyl radicals
348
What do hydroxyl radicals cause in RBCs?
Haemolysis
349
Why are antioxidants needed to eliminate hydroxyl radicals?
They cannot be removed enzymatically
350
How is nitric oxide, which is a free radical, used physiologically in the body?
Used for signalling
351
How is nitric oxide formed?
From arginine by inducible NO synthase
352
What is formed if hydrogen peroxide combines with oxygen?
Peroxynitrite
353
What is peroxynitrite involved in?
Inflammation
354
What exogenous agents can overwhelm the tissue's defence against oxidising agents?
Drugs e.g. antimalarials
| Toxins e.g. paraquat
355
What are the five most common reactive oxygen species?
```
Superoxide
Hydrogen peroxide
Hydroxyl
Nitric oxide
Peroxynitrite
```
356
What are the five cellular defences against ROS?
```
SOD
Catalase
NADPH
Glutathione
Antioxidants e.g. those found in grapes
```
357
Why is glutathione a very effective reducing agent?
Thiol group donates its hydrogen easily
358
How does glutathione act as the first line of defence against ROS?
Donates H from thiol group --> oxidised to glutathione disulphide which can be reduced by GSH reductase to be constantly replenished to glutathione
359
When can glutathione not be reformed in RBCs?
G6PDH deficiency
360
How is NADPH mainly produced?
Pentose phosphate pathway
361
What does NADPH use to act as a second line of defence against ROS?
G6PD
362
What does NADPH replenish?
GSH
363
What other types of antioxidants are there apart from glutathione and NADPH?
Dietary vitamins
Flavenoids
Minerals
364
Which dietary vitamins are antioxidants?
A, C and E
365
Give two examples of flavonoids which are found in coloured fruit and veg.
Polyphenols
| Beta-carotene
366
Name two minerals which may be required by some enzymes for antioxidant function.
Selenium
| Zinc
367
What is lipid peroxidation?
Reaction of unsaturated lipids w/ROS to form lipid peroxide so
368
Why does lipid peroxidation lead to early stages of CVD?
Damages CSM and plaques form as macrophages recognise and engulf faulty lipids
369
What is oxidative burst?
Rapid release of superoxide and hydrogen peroxide from leucocytes to kill local pathogens
370
What is NADPH oxidase?
A very complex protein in CSM that fires rapidly produced ROS inwards
371
What conditions are associated with oxidative stress?
```
Cancer
Emphysema
Pancreatitis
CVD
Crohn's
RA
T1DM
Alzheimer's
Ischaemia/reperfusion injury
```
372
How does reperfusion injury cause oxidative stress?
Clot bust --> sudden increase in oxygen to ischaemic tissue --> increase in ROS
373
What is pharmacodynamics?
What the drug does to the body
374
What is pharmacology?
Study of how chemical agents affect the function of living organisms
375
What is pharmacokinetics?
What the body does to the drug
376
What four things does pharmacokinetics consider?
Absorption
Distribution
Metabolism
Elimination
377
Are most drugs water soluble or lipid soluble?
Lipid
378
Why is a large proportion of a penicillin dose lost in the urine?
It is water soluble
379
Why can most drugs not be excreted directly by the kidney?
Lipid soluble so are filtered out by kidney but then reabsorbed so
380
What path must drugs take to be excreted via the kidney?
Parent drug molecule --> polar, lipid insoluble, water soluble derivative --> excretion via kidney
381
How does the pharmacological activity of metabolites usually compare to the parent drug molecule?
Less active
382
What is special about prodrugs?
They must be metabolised to become active
383
Why might patients belonging to the Chinese population not be able to be treated with codeine?
Lack conversion enzyme so cannot metabolise it to morhpine
384
What is primidone metabolised to?
Phenoarbitone
385
What is the toxic metabolite of pethidine?
Norpethidine
386
What happens during phase I of drug metabolism?
Add or exposure of a reactive group by oxidation, reduction or hydrolysis
387
What is the main site of phase I drug metabolism?
Microsomes on ER in hepatocytes
388
Where, other than the liver, can phase I drug metabolism take place?
GI tract
Kidney
Lung
Plasma
389
Why does heroin have such a short half life?
Its ester bonds are rapidly broken down by cholinesterase enzymes in the plasma
390
Give an example of an opioid drug which skips phase I metabolism.
Morphine
391
What is present in the microsomes of ER in hepatocytes that is used in phase I of drug metabolism?
Cytochrome P450 enzyme system (CYP)
392
What accounts for ~55% of drug metabolism in the phase I pathway?
Isoform CYP3 A4
393
What is abundant in hepatocytes which is a CYP cofactor that has both oxidative and reductive functions?
NADPH
394
What happens in phase II of drug metabolism?
Conjugation - altered molecule is combined w/water soluble group so it can be eliminated by the kidney
395
Where is the most common site of conjugation which uses cytosolic enzymes?
Liver
396
What reactions can be used in phase II drug metabolism?
Glucuronidation
Sulphate conjugation
Glutathione conjugation
397
What high energy form of metabolite is used as a cofactor for glucuronidation?
Uridine diphosohate glucuronic acid
398
What is glucuronic acid?
Metabolite of glucose which is readily available to make drug molecules water soluble
399
What genetic factors can vary drug metabolism in the population?
Polymorphisms
Lack main enzyme for acetylation in phase II - slow acetylators
Low levels of pseudocholinesterase
400
What causes short term muscle relaxants to act for much longer in some individuals?
Have low levels of pseudocholinesterase in plasma
401
What environmental influences vary drug metabolism in the population?
Metabolism of one drug can affect metabolism of another
Inhibition e.g. fruit juices
Induction by an agent of enzymes in the liver
402
Why are smokers and drinkers problematic for anaesthetists?
Smoking and alcohol consumption induces enzymes in the liver so anaesthetics are more rapidly broken down
403
What path do drugs take in the first pass effect?
Lumen of ileum --> venous blood --> hepatic portal vein --> liver
404
What is the first pass effect?
Any drug absorbed into the blood is excessively metabolised by the liver
405
Why are large doses of paracetamol needed?
90% is metabolised by first pass effect so only 10% of a dose is effective
406
What is pharmacoepidemiology?
Study of drug effects in a large population
407
What is pharmacovigilance?
Reporting of adverse drug reactions (ADRs) post-marketing
408
Give two drugs and their effects that were significant to pharmacovigilance.
Thalidomide - affected limb buds which did not arise in animal testing
Mefloquine - no wide malarial resistance but causes lots of side effects
409
What happens to a therapeutic dose of paracetamol?
Undergoes phase II metabolism only - glucuronidation and sulphation
410
Why does paracetamol bypass phase I metabolism?
It already has an OH reactive group
411
What happens in a toxic dose of paracetamol?
Glucuronidation and sulphation are saturated so paracetamol undergoes phase I metabolism
412
What is formed when paracetamol undergoes phase I metabolism?
NAPQI, a toxic metabolite
413
Why is NAPQI formation in paracetamol overdose so dangerous?
It is a toxic metabolite
| It undergoes glutathione conjugation which kills liver cells by oxidative stress
414
How is alcohol dealt with by the body?
90% metabolised
415
What is alcohol converted to as it is metabolised?
Alcohol --> acetylaldehyde --> acetic acid
416
Which enzymes are involved in alcohol metabolism?
Alcohol dehydrogenase
Aldehyde dehydrogenase
CYP2E1
417
What causes hangovers?
Build up of toxic metabolite acetylaldhyde
418
What can acetic acid from alcohol metabolism be used for?
FA and ketone body synthesis
419
What is the metabolism rate for alcohol?
~7 g per hour
420
What action of alcohol dehydrogenase can lead to excess fat deposition, decreased FA oxidation and therefore hypoglycaemia, gout and lactic acidosis?
Decreases NAD+ to NADH ratio
421
What causes fatty liver in alcoholics?
Fat deposition and acetylaldehyde damage
422
What can fatty liver lead to?
Alcoholic hepatitis
| Alcoholic cirrhosis
423
What treatment is given in severe alcohol dependency?
Disulfiram
424
How does Disulfiram work?
Inhibits aldehyde dehydrogenase which causes a build up of acetaldehyde resulting in a week long hangover
425
What do the cost and effects on the CNS in alcoholism cause?
Poor dietary habit which leads to GI tract disturbances such as folic acid deficiency leading to anaemia, vitamin deficiency, diarrhoea and lack of appetite
