New lessons of combinatorial biosynthesis from myxobacteria - The myxothiazol biosynthetic gene cluster of Stigmatella aurantiaca DW4/3-1

The biosynthetic mta gene cluster responsible for myxothiazol formation fro m the fruiting body forming myxobacterium Stigmatella aurantiaca DW4/3-1 wa s sequenced and analyzed. Myxothiazol, an inhibitor of the electron transpo rt via the bc(1)-complex of the respiratory chain, is biosynthesized by a u nique combination of several polyketide synthases (PKS) and nonribosomal pe ptide synthetases (NRPS), which are activated by the 4'-phosphopantetheinyl transferase MtaA. Genomic replacement of a fragment of mtaB and insertion of a kanamycin resistance gene into mtaA both impaired myxothiazol synthesi s. Genes mtaC and mtaD encode the enzymes for bis-thiazol(ine) formation an d chain extension on one pure NRPS (MtaC) and on a unique combination of PK S and NRPS (MtaD), The genes mtaE and mtaF encode PKSs including peptide fr agments with homology to methyltransferases, These methyltransferase module s are assumed to be necessary for the formation of the proposed methoxy- an d beta-methoxy-acrylate intermediates of myxothiazol biosynthesis. The last gene of the cluster, mtaG, again resembles a NRPS and provides insight int o the mechanism of the formation of the terminal amide of myxothiazol, The carbon backbone of an amino acid added to the myxothiazol-acid is assumed t o be removed via an unprecedented module with homology to monooxygenases wi thin MtaG.