Session 3 Flashcards
(64 cards)
0
Q
Describe the key features of pyruvate dehydrogenase reaction
A
- Pyruvate dehydrogenase is a large multi-enzyme complex
- Occurs in mitochondrial matrix (pyruvate shunted across mitochondrial membrane)
- Irreversible because of loss of Carbon dioxide - key regulatory step
- Acetyl CoA cannot be converted back to pyruvate to form glucose in gluconeogenesis
- PDH deficiency causes lactic acidosis
1
Q
What happens to Pyruvate at the end of glycolysis?
A
- Converted to Acetyl CoA by pyruvate dehydrogenase in the mitochondrial matrix
2
Q
What cofactors does pyruvate dehydrogenase require?
A
- FAD
- Thiamine pyrophosphate
- Lipoic acid
- All act catalytically
- Allows complicated reaction to be performed in a controlled manner
3
Q
Why is pyruvate dehydrogenase very sensitive to vitamin B deficiency?
A
- 4 B vitamins are involved in the reaction
4
Q
What inhibits pyruvate dehydrogenase?
A
- Acetyl-CoA (acetyl CoA from B oxidation of fatty acids is used in stage 3 catabolism instead of from glucose) (allosteric inhibition)
- NADH (allosteric
- ATP inhibition)
- Phosphorylation
5
Q
What activates pyruvate dehydrogenase?
A
- Pyruvate
- NAD +
- ADP (allosteric)
- Insulin (promotes dephosphorylation) - causes glucose to increase in cells
6
Q
What is stage 3 of glucose catabolism?
A
- TCA/Krebs cycle
7
Q
What are the main features of the TCA cycle?
A
- Occurs in mitochondria
- Oxidative
- Single pathway for the catabolism of sugars, fatty acids, ketone bodies, alcohol and amino acids
- Acetate is converted to 2 CO2 molecules
- Produces some energy as ATP/GTP
- Produces precursors for other reactions
- Only works in presence of oxygen
8
Q
What is produced by the TCA cycle?
A
- 6 NADH
- 2 FAD2H
- 2 GTP
Per glucose mol (2 turns of cycle)
9
Q
How is the TCA cycle regulated?
A
- ATP/ADP ratio
- NADH/NAD+ ratio
- Isocitrate dehydrogenase catalysts an irreversible reaction and is allosterically inhibited by NADH and activated by ADP a
10
Q
How many ATP molecules are produced by the TCA cycle per glucose molecule?
A
- Approximately 32
11
Q
Give example of intermediates used in anabolism?
A
- Citrate -> fatty acids
- a-ketoglutarate -> amino acids
- Succinate -> amino acids/haem
- Malate -> amino acids
- Oxaloacetate -> amino acids/glucose
12
Q
What and where do other compounds enter the TCA cycle?
A
- Glucose, fatty acids, alcohol and some amino acids enter as Acetyl CoA
- Amino acids also enter directly at a-ketoglutarate, Succinate, Malate and Oxaloacetate
13
Q
How many ATP/GTP molecules have been produced from glycolysis and the TCA cycle per glyph ode molecules?
A
- 2 from glycolysis
- 2 from TCA cycle
- Most of the energy is in the chemical bond energy of the e- in NADH and FAD2H
14
Q
What has happened by the end of stage 3 catabolism?
A
- All C-C bonds broken and C atoms oxidised to CO2
- All C-H binds broken and H atom (H+ and e-) transferred to NAD+ and FAD
15
Q
What are the feature of stage 4 catabolism?
A
- Takes place on the inner mitochondrial membrane
- Involves electron transport and ATP a synthesis
- NADH and FAD2H are re-oxidised
- O2 is required
- Produces large amounts of ATP
16
Q
What processes happen in stage 4 catabolism?
A
- Electron transport: electrons from NADH and FAD2H transferred through a range of carrier molecules to oxygen
- Oxidative phosphorylation: free energy used to drive ATP synthesis
Couples the energy from dissipation of the proton motive force to the synthesis of ATP from ADP
17
Q
How many ATP a molecules are produced with the oxidation of NSDH and FAD2H?
A
- 2 mol NADH: 5 mols ATP
- 2 mol FAD2H: 3 mols ATP
18
Q
How is oxidative phosphorylation regulated?
A
- High ATP/low ADP: lack of substrate (inhibition)
19
Q
What are uncouplers?
A
- Increase the permeability of the inner mitochondrial membrane to protons
- Dissipate the protons gradient, reducing the protein motive force
- No drive for ATP synthesis
- Eg dinitrophenol, dinitrocresol
20
Q
What are inhibitors?
A
- Block electron transport
- Prevents O2 accepting electrons
- Eg cyanide, carbon monoxide
21
Q
What are uncoupling proteins?
A
- Proteins that uncouple electron transport chain from ATP production to produce heat
- UCP1-5
22
Q
Where are uncoupling proteins located?
A
- Inner mitochondrial membrane and allow a leak of protons back across
- UCP 1 (thermogenin) is in brown adipose tissue - important in non-shivering thermogenesis
23
Q
How non-shivering thermogenesis occur in brown adipose tissue?
A
- In response to cold, noradrenaline is released from the sympathetic nervous system
- Stimulates lipolysis releasing fatty acids for B-oxidation
- Forms NADH and FAD2H, driving electron transport and proton motive force
- Noradrenaline also activates UCP1, allowing protons to re-enter matrix, dissipating proton motive force as heat
24
What are other functions of the UCP proteins?
- UCP2 is widely distributed in the body, could be linked to diabetes, obesity, metabolic syndrome and heart failure
- UCP3 is found in skeletal muscle, brown adipose tissue, and is involved in modifying fatty acid metabolism and protecting against reacting species damage
25
What are the key features of lipids?
- Structurally diverse
- Hydrophobic - mostly insoluble in water
- Contain C, H and O (phospholipids contain P and N)
- More reduced that carbohydrates - release more energy when oxidised, requires more Oxygen for oxidation
26
What are the classes of lipids?
- Fatty acid derivatives
- Hydroxy-methyl-glutaric acid derivatives (c6 compound)
- Vitamins
27
What lipids are in fatty acid derivative class?
- Fatty acids: fuel molecule
- Triacylglyerides: fuel storage and insulation
- Phospholipids: components of membranes and plasma lipoproteins
- Eicosanoids: local mediators
28
What lipids are in the hydroxy-methyl-glutaric acid derivatives
- Ketone bodies: water soluble fuel molecules
| - Cholesterol: membranes and steroid hormone synthesis
29
What lipids are in the vitamin class?
- A, D, E and K
30
What are the main features of triacylglyerides?
- Hydrophobic
- Can be stored in anhydrous form
- Stored in adipose tissue
- Utilised in prolonged exercise, starvation, pregnancy
- Storage/mobilisation under hormonal control
31
Where does stage 1 of triacylglyceride occur?
- GI tract
| - Extracellular
32
What happens during stage 1 of triacylglyceride catabolism?
- Hydrolysed by pancreatic lipases in small intestine
| - Forms fatty acids and glycerol
33
What happens to fatty acids from triacylglyerides?
- Converted back to triacylglyerides in GI tract
- Packaged into lipoprotein particle: chylomicrons
- Released into circulation via lymphatics
- Carried to adipose tissue where it is stored as triacylglyeride
- Released as fatty acids when needed
- Carried to tissues as albumin-fatty acid complex
34
What happens in adipose cells when extracellular glucose is low?
- Fatty acids are released (on albumin) as an alternative fuel
35
How is triacylglyeride storage controlled?
- Hormonal control
36
What hormones activate triacylglyeride storage?
- Insulin
37
What hormones inhibit triacylglyeride storage?
- Glucagon
- Adrenaline
- Cortisol
- Growth hormone
- Thyroxine
38
What happens to glycerol after it is hydrolysed from dietary triacylglyerides?
- Enters bloodstream and is transported to the liver
| - Is converted to glycerol phosphate
39
Describe the conversion of glycerol to glycerol phosphate
- Glycerol -> glycerol phosphate
- ATP -> ADP
- Glycerol kinase
40
What happens to the glycerol phosphate after conversion from glycerol?
- Used in triacylglyeride synthesis
| - Converted to dihydroxyacetone phosphate (NAD+ -> NADH) and enters glycolysis
41
What are features of fatty acids?
- Saturated/unsaturated
- Amphipathic
- Some essential fatty acids eg linolenic acid
- Reduced and hydrophobic (good for energy storage)
42
Where does stage 2 of lipid metabolism occur (fatty acids)?
- Mitochondria
43
What happens in fatty acid catabolism?
- Fatty acids are activated outside the mitochondrion (by linking to CoA)
- Transported across inner mitochondrial membrane by the carnitine shuttle
- Cycles through sequence of oxidative relations, removing a C2 at each cycle
44
What happens during fatty acid activation?
- Occurs outside of mitochondria
- Linked to CoA by fatty acyl CoA synthase
- Requires ATP a
45
When do triacylglyerides in adipose tissue undergo lipolysis?
- Stress eg aerobic exercise, starvation, lactation
46
How is lipolysis of triacylglyerides in adipose tissue controlled?
- Enzyme hormone-sensitive lipase
47
What activates lipolysis?
- Glucagon
- Adrenaline
- Cortisol
- Growth hormone
- Thyroxine
48
What inhibits lipolysis?
- Insulin
49
Why do activated fatty acids need the carnitine shuttle to cross the mitochondrial membrane?
- Are hydrophobic
50
What are the features of the carnitine shuttle?
- Regulates rate of fatty acid oxidation as controls entry into mitochondria
- Inhibited by malonyl CoA (prevents newly synthesised fatty acids in cytoplasm from immediately being transported into mitochondria and oxidised)
- Defects: poor exercise tolerance and high levels of triacylglyerides in muscle cells
51
What does the B oxidation of fatty acids require?
- Mitochondrial NAD+ and FAD
| - Oxygen presence
52
What are the features of b oxidation?
- Oxidises
- Removes 2C (acetate) each cycle
- No direct synthesis of ATP
- All intermediates are linked to CoA and C atoms of fatty acid are converted to Acetyl CoA
- More energy derived from fatty acid oxidation than glucose oxidation
53
Where doesn't b oxidation occur?
- Brain
- Red blood cells
- White blood cells
54
What happens to Acetyl CoA (catabolism and anabolism)?
- CO2
- Fatty acids -> triacylglyerides/phospholipids
- Hydroxymethyl glutaric acid (HMG) -> ketone bodies/cholesterol (-> steroid hormones)
55
What ketone bodies are there?
- Acetone
- Acetoacetate
- B-hydroxybutyrate
56
What are the different levels of ketones in the blood plasma?
- Normal: 10 mM
57
Where are ketone bodies synthesised?
- Acetoacetate and B-hyroxybutyrate: liver
| - Acetone: spontaneous decarboxylation of Acetoacetate
58
What are the properties of ketone bodies?
- Water-soluble (allows high plasma concentrations and excretion in urine (ketouria)
- Acetoacetate and B-hydroxybutyrate can cause ketoacidosis in high concentrations in plasma
- Acetone is volition and can be excreted by lungs (can be smelt on breath of untreated type 1 diabetics)
59
How are ketone bodies synthesised?
- Acetyl~CoA -> Hydroxymethyl glutaryl CoA (HMG~CoA) (synthase)
- HMG~CoA -> mevalonate (HMG~CoA reductase) -> cholesterol
- HMG~CoA -> Acetoacetate (Lyase) -> acetone/B-hydroxybutyrate
60
How is ketone body synthesis regulated?
- Fed state ie high insulin:glucagon ratio: Lyase is inhibited/reductase is activated; Cholesterol synthesis activated
- Starvation/diabetes ie low insulin: glucagon ratio: Lyase is activated/reductase inhibited; ketone body synthesis
61
What does ketone body synthesis require?
- Excessive lipolysis of in adipose tissue to supply substrate of fatty acids
- Low plasma insulin:glucagon ratio usually due to a fall in insulin
62
What uses ketone bodies?
- All tissues containing mitochondria including CNS
63
What happens to ketone bodies?
- Converted to Acetyl CoA
| - Oxidised in stage 3 of catabolism
