Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis

Autor(es):Mostrar menos -

Little, Rory ^[1] ; Paiva, Fernanda C. R. ^[2] ; Jenkins, Robert ^[3] ; Hong, Hui ^[1] ; Sun, Yuhui ^[4] ; Demydchuk, Yuliya ^{[1, 5]} ; Samborskyy, Markiyan ^[1] ; Tosin, Manuela ^[3] ; Leeper, Finian J. ^[6] ; Dias, Marcio V. B. ^{[2, 3]} ; Leadlay, Peter F. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Cambridge, Dept Biochem, Cambridge - England

^[2] Univ Sao Paulo, Inst Biomed Sci 2, Dept Microbiol, Sao Paulo, SP - Brazil

^[3] Univ Warwick, Dept Chem, Coventry, W Midlands - England

^[4] Wuhan Univ, Sch Pharmaceut Sci, Key Lab Combinatorial Biosynth & Drug Discovery, Minist Educ, Wuhan, Hubei - Peoples R China

^[5] Bicycle Therapeut Ltd, Babraham Res Campus, Cambridge - England

^[6] Univ Cambridge, Dept Chem, Cambridge - England

• Tipo de documento: Artigo Científico
• Fonte: NATURE CATALYSIS; v. 2, n. 11, p. 1045-1054, NOV 2019.
• Citações Web of Science: 0

Resumo

Enzymes that catalyse remarkable Diels-Alder-like {[}4+2] cyclizations have been previously implicated in the biosynthesis of spirotetronate and spirotetramate antibiotics. Biosynthesis of the polyether antibiotic tetronasin is not expected to require such steps, yet the tetronasin gene cluster encodes enzymes Tsn11 and Tsn15, which are homologous to authentic {[}4+2] cyclases. Here, we show that deletion of Tsn11 led to accumulation of a late-stage intermediate, in which the two central rings of tetronasin and four of its twelve asymmetric centres remain unformed. In vitro reconstitution showed that Tsn11 catalyses an apparent inverse-electron-demand hetero-Diels-Alder-like {[}4+2] cyclization of this species to form an unexpected oxadecalin compound that is then rearranged by Tsn15 to form tetronasin. To gain structural and mechanistic insight into the activity of Tsn15, the crystal structure of a Tsn15-substrate complex has been solved at 1.7 angstrom resolution. (AU)

• Processo FAPESP: 15/09188-8 - Biossíntese de antibióticos poliéteres e aminoglicosídeos: investigação estrutural de enzimas não usuais ou com aplicabilidade em biologia sintética
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/50140-4 - Mechanisms of ring formation in inophore polyether tetronates
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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