"AT-less" Modular PKSs
"AT-less" Modular PKSs
Pseudomonic Acid Biosynthesis. We sequenced a 74 Kb gene cluster from Pseudomonas fluorescens encoding the biosynthesis of the clinically valuable antibiotic pseudomonic acid-A (PA-A).16 The gene cluster encodes a PKS with mixed modular / iterative Type I / Type II functionality. Directed gene knockouts have led to the biosynthesis of numerous new compounds (some of which are shown in red in Scheme 4). The chemical identification of these led to the first understanding of mupirocin biosynthesis involving many new features.17
Scheme 3. Proposed pathway to pseudomonic acid A (PA-A). Compounds shown in red were generated by targeted gene knockout and their structures determined by the Bristol PKS group - assisting in elucidating the proposed biosynthetic pathway.
This work is now being extended to analysis of the gene cluster for the biosynthesis of the thiomarinols, metabolites of the marine bacterium Alteromonas rava. The thiomarinols are hybrid antibiotics containing a close analogue of the pseudomonic acids fused to a holomycin moiety which is an antibiotic in its own right.
1. Characterisation of the mupirocin biosynthetic gene cluster from Pseudomonas fluorescens NCIMB 10856, A.K. El-Sayed, J. Hothersall, S.M. Cooper, E. Stephens, T.J. Simpson and C.M. Thomas, Chem. Biol., 2003, 10, 419-430.
2. Mupirocin H, a Novel Metabolite Resulting from Mutation of the HMG-CoA Synthase Analogue, MupH in Pseudomonas fluorescens, J.-e. Wu, R. J. Cox, J. Crosby, M. P. Crump, J. Hothersall, T. J. Simpson, C. M. Thomas, and C. L. Willis, Chem. Commun., 2007, 2040-2042.