Biosynthesis of lipids

Fatty acids are synthesised by a stepwise process that involves the addition of two-carbon units to form a chain, most commonly of 16-18 carbons. The starting point of fatty acid metabolism is the two-carbon compound

The basic building blocks in the synthesis of fatty acids are acetyl-CoA (two-carbon) and malonyl-CoA (three-carbon). We have encountered acetyl-CoA before, when discussing the TCA cycle; malonyl-CoA is formed by the carboxylation of acetyl-CoA.

Acetyl-CoA + CO2 ^ Malonyl-CoA 2 — carbon 3 — carbon

Carbon dioxide is essential for this step, but is not incorporated into the fatty acid as it is removed in a subsequent decarboxylation step. In order to take part in the biosynthesis of fatty acids, both molecules have their coenzyme A element replaced by an acyl carrier protein (ACP). In a condensation reaction, one carbon is lost as CO2 and one of the ACPs is released. The resulting four-carbon molecule is reduced, with the involvement of two NADPH molecules, to butyryl-ACP. This is then extended two carbon atoms at a time by a series of further condensations with malonyl-ACP (Figure 6.35).

Thus, extending a fatty acid chain by two carbons involves the expenditure of one ATP and two NADPH molecules. The overall equation for the synthesis of a 16-carbon

Figure 6.34 Gluconeogenesis. Non-carbohydrate precursors can feed into a pathway that converts pyruvate to glucose in a series of reactions that are mostly the reverse of glycolysis. Enzymes not found in glycolysis are shown in italics

H3C-

Acetyl-ACP O

Malonyl-ACP O

CO2 O

H3C C C C ACP Acetoacetyl-ACP H2

2NADPH

2NADP O

H3C C C C ACP Butyryl-ACP H2 H2

Figure 6.35 Fatty acid biosynthesis. Acetyl- and malonyl-ACPs condense with the loss of CO2 to give a four-carbon molecule butyryl-ACP. The addition of further two-carbon acetyl groups is achieved by re-entering the pathway and reacting with further molecules of malonyl-ACP

fatty acid such as palmitic acid can be represented:

8 Acetyl-CoA + 7 ATP + 14 NADPH + 6H+ Palmitate + 14 NADP+ + 8 CoA +

Once formed, fatty acids may be incorporated into phospholipids, the major form of lipid found in microbial cells. Recall from Chapter 2 that a phospholipid molecule has three parts: fatty acid, glycerol and phosphate. These last two are provided in the form of glycerol phosphate, which derives from the dihydroxyacetone phosphate of glycol-ysis. Glycerol phosphate replaces the ACP of two fatty acid-ACP conjugates to yield phosphatidic acid, an important precursor for a variety of membrane lipids. The energy for this reaction is provided, unusually, not by ATP but by CTP (cytidine triphosphate).

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