Hyperammonemia blocks which phase of Krebs cycle?
a-Ketoglutarate dehydrogenase REF: Textbook of Biochemistry for Medical Students 6th edition by D. M. Vasudevan page 179, http://en .wikipedia. org/wiki/Citric_acid_ cycle Urea cycle and TCA cycle are interlinked and so it is called as "Urea Bicycle". The absence of a urea cycle enzyme can result in hyperammonemia or in the build-up of one or more urea cycle intermediates, depending on the enzyme that is missing. Excess ammonia has been shown to inhibit the citric acid cycle (Hatch, 1977) One effect of ammonia is the inhibition of the rate limiting TCA cycle enzyme alpha-ketoglutarate dehydrogenase (alphaKGDH) and possibly also pyruvate dehydrogenase, but this has been regarded to be of no quantitative impoance. However, recent studies justify a revision of this point of view. Based on published data, the following sequence of events is proposed. Inhibition of alphaKGDH both enhances the detoxification of ammonia by formation of glutamine from alpha-ketoglutarate and reduces the rate of NADH and oxidative ATP production in astrocytic mitochondria. Substrates Products Enzyme Reaction type Comment 1 Oxaloacetate + Acetyl CoA + H20 Citrate + CoA-SH Citrate synthase Aldol condensation irreversible, extends the 4C oxaloacetate to a 6C molecule 2 Citrate cis-Aconitate + H20 Aconitase Dehydration reversible isomerisation 3 cis-Aconitate + H20 Isocitrate Hydration 4 Isocitrate + NAD+ Oxalosuccinate + NADH + H + Isocitrate dehydrogenase Oxidation generates NADH (equivalent of 2.5 ATP) 5 Oxalosuccinate a-Ketoglutarate + CO2 Decarboxylation rate-limiting, irreversible stage, generates a 5C molecule 6 a-Ketoglutarate + NAD+ + CoA-SH Succinyl-CoA + NADH + H+ + CO2 u-Ketoglutarate dehydrogenase Oxidative decarboxylation irreversible stage, generates NADH (equivalent of 2.5 ATP), regenerates the 4C chain (CoA excluded) 7 Succinyl-CoA + GDP + Pi Succinate + CoA-SH + GTP Succinyl-CoA synthetase substrate-level phosphorylation ADP ATP or ---o. instead of GDP -- GTP,[91 generates 1 ATP or equivalent 8 Succinate + ubiquinone (Q) Fumarate -F ubiquinol (QH2) Succinate dehydrogenase Oxidation uses FAD as a prosthetic group (FAD FADH2 in first --, the step of the reaction) in the enzyme,'91 generates the quivalent of 1.5 ATP 9 Fumarate + H20 L-Malate Fumarase Hydration 10 L-Malate + NAD+ Oxaloacetate + NADH + H+ Malate dehydrogenase Oxidation reversible (in fact, equilibrium ors inalate), generates NADH (equivalent of 2.5 ATP)
Malate dehydrogenase
Isocitrate dehydrogenase
a-Ketoglutarate dehydrogenase
Succinate dehydrogenase