| Malate shuttle allows the recruitment of 2-carbon units from the mitochondrion to the cytoplasm
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The primary molecule required for the synthesis of fatty acids is acetyl-CoA. However, acetyl-CoA is generated in the mitochondria and it cannot freely cross the inner mitochondrial membrane. As said above, fatty acid biosynthesis occurs in the cytosol. The malate shuttle is a mechanism allowing the transfer of 2-carbon units from the mitochondria to the cytosol: it involves the malate-citrate antiporter (Fig. 15.4). Pyruvate derived from glycolysis is decarboxylated to acetyl-CoA in the mitochondria; it subsequently reacts with oxaloacetate in the tricarboxylic acid (TCA) cycle (see Chapter 13) to form citrate. Translocation of a molecule of citrate to the cytosol via the antiporter is accompanied by transfer of a molecule of malate to the mitochondrion. In the cytosol, citrate, in the presence of ATP and CoA, undergoes cleavage to acetyl-CoA and oxaloacetate by citrate lyase. This makes acetyl-CoA available for carboxylation to malonyl-CoA and for the synthesis of fatty acids.The synthesis of fatty acids is also linked to glucose metabolism through the pentose phosphate pathway which is the main provider of NADPH required for lipogenesis. Some NADPH is also generated by the NADP+-linked decarboxylation of of malate to pyruvate by malic enzyme:
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| Figure 15.3 Reactions catalyzed by fatty acid synthase. The cyclical part of the fatty acid biosynthesis is completed six times to release one 16-carbon molecule of palmitate. NADPH, reduced nicotinamide dinucleotide phosphate; pan, pantetheine. |
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