Isocitrate dehydrogenase reaction pathway

The second regulatory site is the isocitrate dehydrogenase reaction. In this case, ADP and NAD+ are allosteric activators of the enzyme. We have called attention to the recurring pattern in which ATP and NADH inhibit enzymes of the pathway, and ADP and NAD+ activate these enzymes. 

Figure 22-4. Sequence of reactions in the oxidation of unsaturated fatty acids, eg, linoleic acid. A -c/s-fatty acids or fatty acids forming A -c/s-enoyl-CoA enter the pathway at the position shown. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrial sources such as glutamate dehydrogenase, isocitrate dehydrogenase,and NAD(P)H transhydrogenase.

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 first step is carboxylation of acetyl CoA to malonyl CoA. This reaction is catalyzed by acetyl-CoA carboxylase [5], which is the key enzyme in fatty acid biosynthesis. Synthesis into fatty acids is carried out by fatty acid synthase [6]. This multifunctional enzyme (see p. 168) starts with one molecule of ace-tyl-CoA and elongates it by adding malonyl groups in seven reaction cycles until palmi-tate is reached. One CO2 molecule is released in each reaction cycle. The fatty acid therefore grows by two carbon units each time. NADPH+H is used as the reducing agent and is derived either from the pentose phosphate pathway (see p. 152) or from isocitrate dehydrogenase and malic enzyme reactions. 

The NADPH required in the reaction is provided primarily by several reactions of the pentose phosphate pathway (Chapter 8). Recall that NADPH is also produced by the reactions catalyzed by isocitrate dehydrogenase and malic enzyme. 

A relatively large quantity of NADPH is required in fatty acid synthesis. A substantial amount of NADPH is provided by the pentose phosphate pathway (see p. 256). Reactions catalyzed by isocitrate dehydrogenase (see p. 285) and malic enzyme (see p. 291) provide smaller amounts. 

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. 

The reductive citric acid cycle is generally considered to be the most energy-efficient CO2 fixation pathway ( 0.6 mol ATP/mol CO2 for pyruvate) [20, 30, 31]. This is reflected by the activity of the pathway s key carboxylases, isocitrate dehydrogenase, a-ketoglutarate ferredoxin oxidoreductase, and pyruvate ferre-doxin oxidoreductase. All three enzymes couple their carboxylation reaction to a subsequent reduction step. Whereas isocitrate dehydrogenase is an NAD(P)H-dependent enzyme, the latter two enzymes use ferredoxin as a reductant (Scheme 9.3) [32-34]. 

It is generally accepted that only NADPH would be able to supply the hydrogen necessary for lipogenesis in the condensation system (Lynen, 1961 Ball, 1966). Lowenstein, therefore, has suggested another pathway for the formation of NADPH in the cytoplasm (Lowenstein, 1961b). It is dependent on the capacity of the cytoplasm to accomplish the first reactions of the tricarboxylic cycle, i.e., the reactions that yield a-ketoglutaric acid. A cytoplasmic NADP-isocitrate dehydrogenase, in contrast to the mitochondrial enzyme, the coen-... 

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