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The Citric Acid Cycle Takes Part in Fatty Acid Synthesis

المؤلف:  Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil

المصدر:  Harpers Illustrated Biochemistry

الجزء والصفحة:  32nd edition.p161-162

2025-06-22

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Acetyl-CoA, formed from pyruvate by the action of pyruvate dehydrogenase, is the major substrate for long-chain fatty acid synthesis in nonruminants (Figure 1). (In ruminants, acetyl-CoA is derived directly from acetate.) Pyruvate dehydrogenase is a mitochondrial enzyme, and fatty acid synthesis is in the cytosol; the mitochondrial membrane is impermeable to acetyl-CoA. For acetyl-CoA to be available in the cytosol, citrate is transported from the mitochondrion to the cytosol, then cleaved in a reaction catalyzed by citrate lyase (see Figure 1). Citrate is only available for transport out of the mitochondrion when aconitase is inhibited by its product and therefore saturated with its substrate, so that citrate cannot be channeled directly from citrate synthase onto aconitase. This ensures that citrate is used for fatty acid synthesis only when there is an adequate amount to ensure continued activity of the cycle. The identity and regulation of the many mitochondrial transport systems (eg, malate, citrate, pyruvate) involved in cataplerosis and anaplerosis pathways are poorly understood, but they likely play a critical regulatory role in these pathways.

Fig1. Participation of the citric acid cycle in provision of cytosolic acetyl-CoA for fatty acid synthesis from glucose.

The oxaloacetate released by citrate lyase cannot reenter the mitochondrion, but is reduced to malate, at the expense of NADH, and the malate undergoes oxidative decarboxylation to pyruvate, reducing NADP+ to NADPH. This reaction, catalyzed by the malic enzyme, is the source of half the NADPH required for fatty acid synthesis (the remainder is provided by the pentose phosphate pathway). Pyruvate enters the mitochondrion and is carboxylated to oxaloacetate by pyruvate carboxylase, an ATP-dependent reaction in which the coenzyme is the vitamin biotin.