Isocitrate dehydrogenase product inhibition

Many examples of product inhibition are to found. Some dehydrogenases are inhibited by NADH (a co-product of the reaction), e.g. PDH and isocitrate dehydrogenase (ICD), which are involved with the glycolysis and the TCA cycle are two such examples. Hexokinase isoenzymes in muscle (but not liver) and citrate synthase are inhibited by their products, glucose-6-phosphate and citrate respectively offering a very immediate fine tuning of reaction rate to match cellular requirements and possibly allowing their substrates to be used in alternative pathways. 

The most important factor in the regulation of the cycle is the NADH/NAD ratio. In addition to pyruvate dehydrogenase (PDH) and oxoglu-tarate dehydrogenase (ODH see p. 134), citrate synthase and isodtrate dehydrogenase are also inhibited by NAD deficiency or an excess of NADH+HT With the exception of isocitrate dehydrogenase, these enzymes are also subject to product inhibition by acetyl-CoA, suc-cinyl-CoA, or citrate. 

The first control site is isocitreUe dehydrogenase. The enzyme is allosteri-cally stimulated by ADP, which enhances the enzyme s affinity for substrates. The binding of isocitrate, NAD , Mg ", and ADP is mutually cooperative. In contrast, ATP is inhibitory, The reaction product NADH inhibits isocitrate dehydrogenase by directly displacing NAD. It is important to note that several steps in the cycle require NAD or FAD, which are abundant only when the energy charge is low. 

Within the citric acid cycle itself, the three control points are the reactions catalyzed by citrate synthase, isocitrate dehydrogenase, and the a-ketoglutarate dehydrogenase complex. We have already mentioned that the first reaction of the cycle is one in which regulatory control appears, as is to be expected in the first reaction of any pathway. Gitrate synthase is an allosteric enzyme inhibited by ATP, NADH, succinyl-GoA, and its own product, citrate. 

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