Metabolism L3.1 Flashcards
Diagram showing overview of Catabolism
State location of glycolysis
Cytosol
Describe the end of stage 2 catabolism
Pyruvate (end product of aerobic glycolysis) does not directly enter TCA cycle (stage 3 catabolism)
Pyruvate must be transported from cytosol to mitochondria via PYRUVATE TRANSLOCASE
(In mitochondrial matrix, pyruvate converted to acetyl CoA)
Describe how pyruvate is converted into acetyl CoA in mitochondrial matrix during end of stage 2 catabolism
Pyurvate undergoes oxidative decarboxylation
(IRRERVSIBLE) by pyruvate dehydrogenase
State cofactors required by pyruvate dehydrogenase
Thiamine phosphate
FAD
NAD+
CoA
Lipoic acid
State the source of cofactors required by pyruvate dehydrogenase
Vitamin B (B1, b3, B5)
State why converstion of pyruvate to Acetyl CoA is sensitive to vit B deficiencies
Pyruvate to Acetyl Coa = oxidative decarboxylation reaction by Pyruvate Dehydrogenase
This enzyme requires cofactors, (thiamine, CoA, NAD+, FAD)
These cofactors are provided from Vit B (B3, B5)
Diagram showing regulation of reaction catalysed by Pryuvate Dehydrogenase
How is PDH regulated (activated and inhibited) during conversion of pyruvate to acetyl CoA
Activated by:
- Pyruvate
- CoA
- NAD+
- ADP
- Insulin
Inhibited by:
1. Aceytol CoA
2. ATP
3. NADH+ + H+
State cause of Pyruvate Dehydrogenase Deficiency
Genetic defect in pyruvate dehydrogenase
State effects of pyruvate dehydrogenase deficiency
No acetyl CoA
So, no energy release in aerobic metabolim
To compensate, anaerobic metabolism occurs, (reduction of pyruvate to lactate), too much lactate then accumulates in blood, leads to LACTIC ACIDOSIS
Lactic acidosis recap
State where TCA cycle occurs
Mitochondria
Summary of TCA cycle
Diagram showing TCA cycle
Only memorise important reactions
Diagram showing TCA cycle: GTP (ATP) synthesis + reducing power release
Why are there 2 x TCA cycles per mole of glucose?
For each mole of glucose, 2 moles of pyruvate are produced in glycolysis.
Therefore, the 2 pyruvates are both oxidatvely decarboxylised into Acetyl CoA molecules.
So, 2 x Acetyl CoA, therefore, 2 rounds of TCA cycle
Stage 1 of TCA Cycle
Acetyl CoA (2C) undergoes condensation with oxaloacetate (4C) to form citrate (6C)
CITRATE SYNTHASE
Stage 4 of TCA Cycle
Oxidative decarboxylation of isocitrate (6C) to form alpha-ketoglutarate (5C)
ISOCITRATE DEHYDROGENASE
NADH + H+ produced
Stage 5 of TCA cycle
Oxidative decarboxylation of alpha-ketoglutarate to form succinyl-CoA (4C)
(alpha-ketoglutarate dehydrogenase)
NADH + H+ produced
Stage 6 of TCA cycle
Succinyl-CoA cleaved to form
1. Succinate
2. CoA
by subtsrate phosphorylation
THIOKINASE
(GTP formed)
Stage 7 of TCA cycle
Oxidation of succinate to fumerase
Succinate Dehydrogenease
FADH2 produced
Stage 8 of TCA cycle
Fumerate hydrated to malate
FUMERASE
Stage 9 of TCA cycle
Malate oxidised to oxaloacertate
Malate dehydrogenease
NADH + H+ produced
State points of regulation within TCA cycle
Reactions 1,4, 5
- Citric synthase
Activated: Acetyl CoA
Inhibited: Citrate - Isocitrate dehydrogenase
Activated: ADP
Inhibited: ATP, NADH + H+ - alpha-ketoglutarate dehydrigenase
Activated: ADP
Inhibited: ATP, NADH + H+, succinyl CoA
TCA cycle provides intermediates for anabolic processes
State the location of oxidative phoshorylation
Mitochondria
(inner mitochondrial membrane)
State conditions required for oxidative phosphorylation
O2
Summarise oxidative phosphorylation
Electrons from NADH+ + H+ and FADH2 transferred to O2.
The carriers above are now re-oxidised to NAD+, FAD)
Free energy from electron transport drives synthesis of ATP
Describe oxidative phosphorylation
2 phases: 1. Electron transport 2. ATP synthesis
Electrons transferred from NADH+ + H+ and FADH2 through series of protein complexes to O2
(IN MORE DETAIL: PCI + PCII pass electrons from NADH+ + H+ and FADH2 TO PCIII and PCIV. PCIV passes electrons to oxygen, which forms water). PCI, PCIII, PCIV pump H+ from matrix to intermembrane space using free energy released during electron transport)
This releases energy
30% of this energy used to move H+ across membrane and rest is lost as heat
Movement of H+ creates H+ conc gradient cross inner membrane (proton motive force)
H+ conc gradient dissipated (reduced) by ATP synthase
H+ pumped into matrix (favoured by electrochemical gradient)
Energy released from flow of H+ used by ATP synthase to synthesise ATP from ADP and Pi.
Energetics of oxidative phosphorylation
Describe the net synthesis of ATP from glucose
Compare oxidative vs substrate level phosphorylation
Describe Regulation of oxidative phosphorylation
High ATP - Rate of oxidative phosphorylation decreased.
No substrate for ATP synthase.
Conc. of H+ atoms No, inward flow of H+ atoms stops. Prevents firther H+ pump, stops electron transport
Low ATP - Rate of oxidative phosphorylation increased
Describe what factors affect the efficiency of oxidative phosphorylation
Tightness of coupling og electron transport to ATP synthesis.
Coupling depend s on tissues:
- Higher in tissues with higher energy demand (exercising muscle tissue)
Uncoupling occurs in brown adipose tissue.
Therefore, oxidative phosphorylation is less efficient
This allows extra heat generation rather than ATP
State conditions under which oxidative phosphorylation can be inhibited
- Anaerobic
- Excessive reactive oxygen species
- Cabron monoxide, cyanide (inhibit electron transport)
Cyanide - prevents acceptance of electrons by O2
therefore, no electrochemical gradient across mitochondrial membrane, no ATP synthesis
Leads to death
State the role of synthetic uncouplers
e.g. 2,4 dinitrophenol (DNP)
(uncoupling electron transport from ATP synthesis)
- Increase permeability of mitochondrial inner membrane to H+
- Dissipates H+ conc gradient
- No movement of H+ / No proton motive force
- Uncouples electron transport from ATP synthesis
- No ATP synthesis,increased heat production, leads to death
Why was DNP used medically as a weight loss drug?
Increased metabolic rate, increase heat production
Why was DNP banned from human consumption?
e.g. 2,4 dinitrophenol (DNP)
(uncoupling electron transport from ATP synthesis)
- Increase permeability of mitochondrial inner membrane to H+
- Dissipates H+ conc gradient
- No movement of H+ / No proton motive force
- Uncouples electron transport from ATP synthesis
- No ATP synthesis,increased heat production, leads to death
Describe the process of uncoupling in brown adipose tissue
Brown adipose tissue has UCP1 (uncoupling protein - thermogenin) (present in inner mitochindrial membrane)
UCP-1 activated in response to cold / stress
1. Noradrenaline released from sympathetic nervous system
2. Binds to beta adrenergic receptros on BAT
3. Stimulates hydrolysis of triacylglycerols relasing fatty acids
4. Fatty acids oxidised in mitochondria, providing reducing power for oxidatiove phosphorylation
5. Fatty acids activate UCP1, transports H+ from intermembane space into matrix, but no ATP synthesis
6. Electron transport uncoupled from ATP synthesis. Energy from dissipation of H+ conc gradient used to generate heat
This process is known as NON-SHIVERING THERMOGENESIS.
State causes of oxidative phosphorylation diseases
Mutations in mitochondrial DNA (greater mutation rate than nuclear DNA)
State causes and symptoms of Leber hereditary optic neuropathy (LHON)
Mutation in gene coding for PTC 1
Presnets with loss of vision
State causes and symptoms of Leigh syndrome (subacute necrotising encephalopathy)
Mutation in gene coding for ATP synthase
Presents with progressive loss of mental and physical abilities in infancy
