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.