The putative elaiophylin biosynthetic gene cluster in Streptomyces sp DSM4137 is adjacent to genes encoding adenosylcobalamin-dependent methylmalonyl CoA mutase and to genes for synthesis of cobalamin

A type I PKS gene probe obtained from RAPB of the rapamycin producer Streptomyces hygroscopicus, strongly hybridised to 92 out of 1120 cosmids from a genomic library of the elaiophylin-producing strain Streptomyces sp. DSM4137. Partial cosmid sequencing suggested the presence of 10 separate sequences encoding type I PKS genes. One entire DNA sequence was obtained and found exactly to match the gene organisation expected for the biosynthesis of the unusual macrodiolide polyketide elaiophylin. The putative elaiophylin gene cluster contains five large open-reading frames encoding typical modular polyketide synthases, which together catalyse the synthesis of the octaketide monomer of elaiophylin. Other genes were identified that would be required for provision of the ethylmalonate extender unit, for the synthesis and attachment of 2-deoxy-L-fucose and in regulation, or in export of the product. Immediately adjacent to the putative elaiophylin biosynthetic gene cluster is a 30kbp region containing the gene for adenosylcobalamin-dependent methylmalonyl CoA mutase and also genes involved in the biosynthesis of the cobalamin cofactor. Analysis of the latter gene set confirms the view that cbiD of the anaerobic pathway and cobF in the aerobic pathway catalyse the same methylation of precorrin-5. The proximity of these genes to the putative elaiophylin gene cluster can best be rationalised if in this organism succinyl-CoA is a significant source of the methylmalonate units for complex polyketide biosynthesis. (C) 2004 Published by Elsevier B.V.