| Carboxylation of acetyl-CoA to malonyl-CoA is the committed step of fatty acid synthesis
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In the first stage of fatty acid biosynthesis, acetyl-CoA, mostly derived from carbohydrate metabolism, is converted to malonyl-CoA under the action of the acetyl-CoA carboxylase (Fig. 15.1). This is a biotin-dependent enzyme with distinct enzymatic functions and a carrier protein function: its subunits serve as a biotin carboxylase, a transcarboxylase, and a biotin-carboxyl-carrier protein. The enzyme is synthesized in an inactive protomer form (each protomer containing the above subunits), a molecule of biotin, and a regulatory allosteric site for the binding of citrate (a Krebs cycle metabolite) or of palmitoyl-CoA (the end-product of the fatty acid biosynthetic pathway). The reaction itself takes place in stages: first there is the carboxylation of biotin, involving adenosine triphosphate (ATP), and this is followed by the transfer of this carboxyl group to acetyl-CoA to produce the end-product of the reaction, the malonyl-CoA. At this stage, the free enzyme-biotin complex is released.
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| Incidentally, to synthesize fatty acids with an odd-number of carbons, propionyl-CoA is used as a substrate.
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| This key lipogenic enzyme is subject to both short-term and long-term control
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| Figure 15.1 Conversion of acetyl-CoA to malonyl-CoA. Acetyl-CoA carboxylase is covalently attached to biotin, which is carboxylated using a molecule of ATP. The enzyme requires the presence of citrate for polymerization to its active form. It is also regulated by insulin, independently of the citrate-stimulated polymerization. cAMP, cyclic adenosine monophosphate. |
| The protomers of the acetyl-CoA carboxylase polymerize in the presence of citrate or isocitrate, producing the active form of the enzyme. The polymerization is also inhibited by palmitoyl-CoA at the same allosteric site. The respective stimulatory and inhibitory effects of citrate and palmitoyl-CoA are
entirely logical: under conditions of high citrate concentration, energy storage is desirable, but when the product of the pathway (palmitoyl-CoA) accumulates, a decrease in synthesis of fatty acids is appropriate. There is an additional control mechanism: phosphorylation/dephosphorylation of the enzyme molecule. This involves hormone-dependent protein phosphatase/kinase (see Fig. 15.1). Phosphorylation inhibits the enzyme, and dephosphorylation activates it. These effects are independent of the effects of citrate or palmitoyl-CoA. Phosphorylation of the enzyme is stimulated by glucagon and epinephrine, and dephosphorylation by insulin.
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| The carboxylation of acetyl-CoA to malonyl-CoA is the committed step of fatty acid synthesis. This is why this enzyme is under such strict short-term regulation. Longer-term control also exists and is exerted by the induction or repression of enzyme synthesis effected by diet: synthesis of acetyl-CoA carboxylase is upregulated under conditions of high-carbohydrate/low-fat intake, whereas starvation or high-fat/low-carbohydrate intake leads to downregulation of synthesis of the enzyme.
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