Biosynthesis and elongation of short- and medium-chain-length fatty acids

Short- and medium-chain-length fatty acids (FAs) are important constituents of a wide array of natural products. Branched and straight short-chain-len gth FAs originate from branched chain amino acid metabolism, and serve as p rimers for elongation in FA synthase-like reactions. However, a recent mode l proposes that the one-carbon extension reactions that utilize 2-oxo-3-met hylbutyric acid in leucine biosynthesis also catalyze a repetitive one-carb on elongation of short-chain primers to medium-chain-length FAs. The existe nce of such a mechanism would require a novel form of regulation to control carbon flux between amino acid and FA biosynthesis. A critical re-analysis of the data used to support this pathway fails to support the hypothesis f or FA elongation by one-carbon extension cycles of ar-ketoacids. Therefore, rye tested the hypothesis experimentally using criteria that distinguish b etween one- and two-carbon elongation mechanisms: (a) isotopomer patterns i n terminal carbon atom pairs of branched and straight FAs resulting from di fferential labeling with [C-13]acetate; (b) [C-13]threonine labeling patter ns in odd- and even chain length FAs; and (c) differential sensitivity of e longation reactions to inhibition by cerulenin. All three criteria indicate d that biosynthesis of medium-chain length FAs is mediated primarily by FA synthase-like reactions.