Enzyme-Catalyzed Spiroacetal Formation in Polyketide Antibiotic Biosynthesis

Autor(es)

Bilyk, Oksana ; Oliveira, Gabriel S. ; de Angelo, Rafaela M. ; Almeida, Michell O. ; Honorio, Kathia Maria ; Leeper, Finian J. ; Dias, Marcio V. B. ; Leadlay, Peter F.

• Tipo de documento: Artigo Científico
• Fonte: Journal of the American Chemical Society; v. 144, n. 32, p. 9-pg., 2022-08-03.

Resumo

A key step in the biosynthesis of numerous polyketides is the stereospecific formation of a spiroacetal (spiroketal). We report here that spiroacetal formation in the biosynthesis of the macrocyclic polyketides ossamycin and oligomycin involves catalysis by a novel spiroacetal cyclase. OssO from the ossamycin biosynthetic gene cluster (BGC) is homologous to OlmO, the product of an unannotated gene from the oligomycin BGC. The deletion of olmO abolished oligomycin production and led to the isolation of oligomycin-like metabolites lacking the spiroacetal structure. Purified OlmO catalyzed complete conversion of the major metabolite into oligomycin C. Crystal structures of OssO and OlmO reveal an unusual 10-strand beta-barrel. Three conserved polar residues are clustered together in the beta-barrel cavity, and site-specific mutation of any of these residues either abolished or substantially diminished OlmO activity, supporting a role for general acid/general base catalysis in spiroacetal formation. (AU)

• Processo FAPESP: 18/00351-1 - Biologia Estrutural aplicada às enzimas envolvidas na biossíntese de produtos naturais: aplicações biotecnológicas e entendimento molecular de reações enzimáticas pouco usuais
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/03850-9 - Parede celular micobacteriana: estudo estrutural e estratégias de inibição de enzimas relacionadas com sua biossíntese e regulação
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular