Novel inhibitors of the condensing enzymes of the Type II fatty acid synthase of pea (Pisum sativum)

The type II fatty acid synthases (FASs) of higher plants (and Escherichia c oli) contain three condensing enzymes called beta-ketoacyl-ACP synthases (K AS), where ACP is acyl-carrier-protein. We have used novel derivatives of t he antibiotic thiolactomycin to inhibit these enzymes. Overall de novo fatt y acid biosynthesis was measured using [1-C-14]acetate substrate and chloro plast preparations from pea leaves, and [1-C-14]laurate was used to disting uish between the effects of the inhibitors on KAS I from those on KAS II. I n addition, the activities of these enzymes, together with the short-chain condensing enzyme, KAS III, were measured directly. Six analogues were test ed and two, both with extended hydrocarbon side chains, were found to be mo re effective inhibitors than thiolactomycin. Incubations with chloroplasts and direct assay of the individual condensing enzymes showed that all three compounds inhibited the pea FAS condensing enzymes in the order KAS II > K AS I > KAS III. These results demonstrate the general activity of thiolacto mycin and its derivatives against these FAS condensation reactions, and sug gest that such compounds will be useful for further detailed studies of inh ibition and for use as pharmaceuticals against Type II FASs of pathogens.