We have obtained a purified polyketide synthase system, derived from DEBS, which retains catalytic activity. This approach opens the way for mechanistic and structural analyses of active multienzymes derived from any modular polyketide synthase.

Although a broad range of variation in the starter residue is acceptable, the substrate specificity of module 2 of a typical modular PKS in vitro is relatively intolerant of changes at C-2 and C-3. This will restrict the usefulness of approaches to synthesise novel erythromycins using synthetic diketides in vivo. The use of synthetic beta-keto diketides in vivo deserves to be explored.

Genetic engineering of theerythromycin polyketide synthase (PKS), to generate the DEBS 1 protein with a fused thioesterase domain (DEBS 1-TE), followed by expression in Streptomyces coelicolor, resulted in a mutant which produces a small quantity of the erythromycin triketide as a lactone, but the major product is the corresponding nor-analogue derived from acetate rather than propionate as the starter acid.

The four stereoisomers of 3-hydroxy-2-methylpentanoic acid (1a±d) and the structurally modified acids 1e±j have been synthesised enantiospecifically and converted into p-nitrophenyl ester and thioester derivatives; as the activated derivatives; they are available for investigations into the substrate selectivity of polyketide synthase (PKS) domains.

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