Metabolism
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Do we need to synthesise fatty acids?
Key points from this exercise:
The first committed step for fatty acid biosynthesis is carboxylation of acetyl CoA to malonyl CoA; of the 16 carbons in palmitate, only carbons 14 and 15 arise from acetyl CoA; the remainder come from malonyl CoA.
The coenzyme for acetyl CoA carboxylase is the vitamin biotin.
The carboxyl group that was added to acetyl CoA to form malonyl CoA is lost as carbon dioxide in the next reaction of fatty acid synthesis.
Mammalian fatty acid synthase is a large protein with multiple active sites; the growing fatty acid chain is chanelled from one active site to the next by the flexible acyl carrier protein. The prosthetic group of the acyl carrier protein is derived from the vitamin pantothenic acid and the amine cysteamine. Like CoA, this prosthetic group forms a thio-ester with the carboxyl group of fatty acids and derivatives.
The first reaction of fatty acid synthetase is condensation between malonyl ACP and acetyl CoA, to form acetoacetyl ACP.
Acetoacetyl ACP is reduced to hydroxybutyryl ACP, with NADPH as the reductant.
Hydroxybutyryl CoA undergoes dehydration to yield a carbon-carbon double bond between carbons 2-3.
The unsaturated fatty acyl ACP is reduced to a saturated fatty acyl ACP (butyryl ACP in the first cycle of reactions), again with NADPH as the reductant.
The reaction cycle continues with the addition of a further malonyl ACP to the growing fatty acyl ACP until the final product is palmitoyl ACP (C16:0), which is transferred onto CoA, forming palmitoyl CoA and leaving the ACP free to bind another acetyl group and begin the sequence of reactions again.
Although there is intermediate formation of a 2-3 unsaturated fatty acyl ACP intermediate, the complete sequence of reactions must occur, so unsaturated fatty acids cannot by synthesised by the cytosolic fatty acid synthase.
Palmitoyl CoA formed by the cytosolic fatty acid synthase can undergo chain elongation and desaturation in the endoplasmic reticulum to synthesise long-chain saturated and polyunsaturated fatty acids.
Mammalian enzymes can introduce a carbon-carbon double bond between an existing double bond and the carboxyl group of the fatty acid, but not between an existing double bond and the methyl group. This means that there is a requirement for a dietary source of n-3 and n-6 polyunsaturated fatty acids. There is a mammalian delta-9 desaturase that can synthesise oleate (C18:1 n-9) from stearate (C18:0).
The same desaturases and elongases act on n-3, n-6 and n-9 fatty acids, so there is competition between them. This means that the balance of n-3 : n-6 polyunsaturated fatty acids in the diet is important.
The C20 n-3 and n-6 polyunsaturated fatty acids are precursors for the prostaglandins and other eicosanoids. The two families (n-3 and n-6) have different physiological actions, so that again the balance of n-3 : n-6 polyunsaturated fatty acids in the diet is important.