Isocitrate dehydrogenase inhibitor

Direct kinetic assays are the only valid methods for the measurement of activators and inhibitors and calibration plots of the percentage activation or inhibition by known amounts of the substance can be made. Examples of inhibition assays include the quantitation of organophosphorus pesticides using the inhibition of cholinesterase (EC 3.1.1.7) while manganese can be measured in amounts as low as 1 X 10-12 mol using its activating effect on isocitrate dehydrogenase (EC 1.1.1.41). 

The same intermediates of glycolysis and the citric acid cycle that activate isocitrate dehydrogenase are allosteric inhibitors of isocitrate lyase. When energy-yielding metabolism is sufficiently fast to keep the concentrations of glycolytic and citric acid cycle intermediates low, isocitrate dehydrogenase is inactivated, the inhibition of isocitrate lyase is relieved, and isocitrate flows into the glyoxylate pathway, to be used in the biosynthesis of carbohydrates, amino acids, and other cellular components. 

Other forms of vanadium have been implicated in the stimulation of the plasma membrane vanadate-dependent NAD(P)H oxidation reaction. Decavanadate has been shown to be a more potent stimulator of the vanadate-dependent NADH oxidation activity than added orthovanadate [30,31], Interestingly, decavanadate reductase activity has been found to be an alternative activity of an NADP-specific isocitrate dehydrogenase [32], Diperoxovanadium derivatives have also been shown to be involved in this type of reaction [33,34], Decavanadate may play a role in the biological role of vanadium, as it is found in yeast cells growing in the presence of orthovanadate [8] and is a potent inhibitor of phosphofructokinase-1, the control step of glycolysis, and other metabolic reactions [35],... 

X1B-X14), and NADP-linked isocitrate dehydrogenase SIS, S16). Numerous studies have been carried out with isolated mitochondria to identify the source of NADPH for 11 -hydroxylation by studying the effect of inhibitors and uncouplers of oxidative phosphorylation in the presence of different hydrogen donors (83, 19S, SIO, SIS, SI4-SSS). Part of this work was inconclusive since several complicating features in the metabolism of adrenocortical mitochondria were insufficiently taken into account such as secondary inhibitory effects of the substrates, inhibitors, or uncouplers used 83, SI4, SSO, SSS) the requirement of transport of substrates across the mitochondrial membrane SS3, SS4) and the possibility of intramitochondrial dismutation reactions SS3). 

Figure 4-11. The TCA cycle and the precursors of acetyl CoA. ICDH = isocitrate dehydrogenase PDH= pyruvate dehydrogenase ETC = electron transport chain = activator 0 = inhibitor. The ( ) indicates that the thioesters acetyl CoA and succinyl CoA are high-energy compounds.

Beach, R.L., Aogaichi, T. and Plaut, G.W.E. (1977), Identification of D-threo-a-methylisocitrate as stereochemically specific substrate for bovine heart aconitase and inhibitor of TPN-linked isocitrate dehydrogenase. J. Biol. Chem., 252,2702. 

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