Enzymology Of Pyran Ringa Formation In Salinomycin Biosynthesis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Tetrahydropyran rings are a common feature of complex polyketide natural products, but much remains to be learned about the enzymology of their formation. The enzyme SalBIII from the salinomycin biosynthetic pathway resembles other polyether epoxide hydrolases/cyclases of the MonB family, but SalBIII plays no role in the conventional cascade of ring opening/closing. Mutation in the salBIII gene gave a metabolite in which ringA is not formed. Using this metabolite invitro as a substrate analogue, SalBIII has been shown to form pyran ringA. We have determined the X-ray crystal structure of SalBIII, and structure-guided mutagenesis of putative active-site residues has identified Asp38 and Asp104 as an essential catalytic dyad. The demonstrated pyran synthase activity of SalBIII further extends the impressive catalytic versatility of + barrel fold proteins.54461362213625BBSRC [BB/J007250/1]University of Cambridge (Overseas Research Studentship)Todd-Raphael FundFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2010/15971-3, 2011/17510-6