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Metabolic regulation
Uni of Notts, Signalling & Metabolic Regulation, Year 2, Topic 7
| Term | Definition |
|---|---|
| PDC | Pyruvate Dehydrogenase Complex. Irreversibly commits pyruvate to the TCA cycle by decarboxylating it and associating it with CoA |
| Randle cycle (+why it's needed) | Cross-inhibition activity between fatty acid & glucose anabolism in the heart & skeletal muscles since FAs produce more ATP per carbon whereas glucose produces more ATP per O2 |
| PDC general structure | 4-5mDa multi-enzyme complex, looks like little dots clustered together with 5-coenzymes and 3 main enzymes (E1-3) |
| PDH enzymes: E1, E2, E3 | E1 = pyruvate carboxylate E2 = Dihydrolipoyl transacetylase E3 = Dihydrolipoyl dehydrogenase |
| PDH coenzymes: 5 | Thiamine pyrophosphate (TPP) - Pyrophosphorylated B1 Lipoamide - 10C fatty acid with 2 sulfhydryl groups CoA - Pantothenic acid, B5 FAD+ - Riboflavin, B2 NAD+ - Niacin, B3 |
| Unique function of lipoamide | The 2 sulfydryl groups attach together in their oxidised state but, when reduced by pyruvate, opens up the S-S bond to turn the molecule into dihydrolipolic acid with E2 and then E3 used it to reduce NAD+ |
| Steps of PDH committal of pyruvate reaction (4) | 1. E1 decarboxylates, TPP binds hydroxyethyl 2. hydroxyethyl-TPP transfers to lipoamide at E2 causing a redox making acetyl dihydrolipoyl 3. CoASH attacks the acetate making acetyl-CoA 4. dihydrolipoamide reduces FAD+ at E3 which then reduces NAD+ |
| PDC phosphorylation regulation | PDC-kinase phosphorylates 3 serine residues, inhibits activity. PDK is activated by high energy substrates (NADH, AcCoA, ATP) & inhibited by DCA, pyruvate, CoASH, & ADP |
| Role of insulin in PDC | Upregulates the activity of PDC-phosphatase to increase PDC activity by dephosphorylation |
| DCA | Dichloroacetate. Inhibits PDK, preventing phosphorylation, increases the pyruvate being committed even in high energy environments |
| Using DCA to treat illnesses | Illnesses such as peripheral vascular disease cause blockages in the extremities, lower oxygen favours anaerobic over TCA causing issues so DCA is given with vasodilators, forces PDC to work |
| Citrate synthesis reaction (aldol condensation) | Citrate synthase (CS) is induced fit, oxaloacetate must bind first. Removes a proton from acetate making it enol, it attacks the OAA carbonyl to form citryl CoA thioester which is hydrolysed to citric acid. Competitively inhibited by succinyl CoA |
| Significance of isocitrate dehydrogenase | Rate limiting step of the TCA cycle, produces alpha-ketoglutarate. Regulated by high energy substrates & activated by ADP |
| Alpha-Ketoglutarate dehydrogenase parallels with PDC | Homologous to PDC except with differing E1 & E2 regions to accommodate for a larger carbon chain molecule |
| Diabetic lack of PDC control | PDC indirectly inhibited by not activating PDP causing phosphorylation. Lack of insulin means more fatty acids, Randle cycle inhibits glucose metabolism. Body detects glucose scarcity |
Created by:
Denny12
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