Malic enzyme, fatty acid synthesis

In animals and fungi there is a similar dichotomy. NADPH can be generated by cytosolic malic enzyme which catalyses the reaction malate + NADP+ — pyruvate + COg + NADPH. Cytosolic malate derives from the following successive reactions the pyruvate/ citrate shuttle on the mitochondrial inner membrane takes pyruvate to the mitochondrion in exchange for citrate cytosolic ATP citrate lyase catalyses ATP + citrate + CoA-SH —> acetylCoA (CH3CO-S-C0A) + oxaloacetate and cytosolic malate dehydrogenase, which catalyses NADH + oxaloacetate NAD+ + malate. This scheme provides both acetylCoA and NADPH for subsequent long chain fatty acid synthesis (see section on Fatty acid synthesis ). 

The KQ is influenced by the net rate of fatty acid biosynthesis. Fatty acid synthesis involves the conversion of carbohydrate, via the acetyJ-CoA intermediate, to long-chain fatty acids. The synthesis of fatty acids requires reduced NADP as a co/ac-tor. It involves the consumption of two molecules of NADPH + H+ for each 2-carbon unit incorporated into the fatty acid. The NADPH + H is supplied by two separate pathways the pentose phosphate pathway (PPP) and the malic enzyme/citrate Lyase pathway. 

The malic enzyme/citrate lyase pathway is shown in Figure 5.10. The 2-carbon units acetyl groups) for fatty acid synthesis are supplied by the activity of citrate lyase, which may be considered an enzyme of fatty acid biosynthesis. The reduced NADP is Supplied at the point of malic enzyme. Figure 5.10 reveals no net production or utilization of NAD in the cytoplasm. The NADPH + H generated in the cytoplasm is used for fatly acid synthesis, which regenerates NADP. One molecule of CO is produced in the cytoplasm. The diagram reveals no net production or utilization of CO in the mitochondrion. One molecule of NAD is... 

NADPH, which provides the reducing equivalents for fatty acid synthesis, is produced by the inducible malic enzyme and by the inducible enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. 

When citrate, a citric acid cycle intermediate, moves from the mitochondrial matrix into the cytoplasm, it is cleaved to form acetyl-CoA and oxaloacetate by citrate lyase. The citrate lyase reaction is driven by ATP hydrolysis. Most of the oxaloacetate is reduced to malate by malate dehydrogenase. Malate may then be oxidized to pyruvate and CO, by malic enzyme. The NADPH produced in this reaction is used in cytoplasmic biosynthetic processes, such as fatty acid synthesis. Pyruvate enters the mitochondria, where it may be converted to oxaloacetate or acetyl-CoA. Malate may also reenter the mitochondria, where it is reoxidized to form oxaloacetate. 

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. 

The oxaloacetate can be reduced to malate by NADH and then oxidized by malic enzyme to form pyruvate and NADPH. The latter is needed for fatty-acid synthesis. 

F. 33.9. Sources of NADPH for fatty acid synthesis. NADPH is produced by the pentose phosphate pathway and by malic enzyme. OAA = oxaloacetate. 

Fig. 1. Pathway of fatty acid synthesis from glucose in animal tissues. The key enzymes or enzyme systems involved are (1) pyruvate dehydrogenase, (2) pyruvate carboxylase, (3) citrate synthase, (4) citrate translocation system, (5) citrate cleavage enzyme, (6) acetyl-CoA carboxylase, (7) fatty acid synthetase, (8) 3-phosphoglyceraldehyde dehydrogenase, (9) malate dehydrogenase, (10) malic enzyme, (11) hexose monophosphate shunt.

Figure 3.1 Metabolic origin of plastid carbon source and enzyme cofactors required for de novo fatty acid synthesis, (a) Glycolytic enzymes (b) pyruvate kinasec (EC 2.7.1.40) (c) pyruvate kinasep (EC 2.7.1.40) (d) phosphoenolpyruvate (PEP) carboxylase (EC 4.1.1.31) (e) L-malate dehydrogenase (EC 1.1.1.37) (f) malic enzyme (EC 1.1.1.40) (g) pyruvate dehydrogenase (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4).

Today we recognize that the malic enzyme serves in fatty acid synthesis by generating... 

The ketoacyl-ACP is then reduced to yield a hydroxyl group. In turn, this is dehydrated to yield a carbon-carbon double bond, which is reduced to yield a saturated fatty acid chain. Thus, the sequence of chemical reactions is the reverse of that in P-oxidation (section 5.5.2). For both reduction reactions in fatty acid synthesis, NADPH is the hydrogen donor. One source of this NADPH is the pentose phosphate pathway (section 5.4.2) and the other is the oxidation of malate (arising from oxaloacetate) to pyruvate, catalysed by the malic enzyme (see Figure 5.27). 

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