Iterative Mechanism of Macrodiolide Formation in the Anticancer Compound Conglobatin

Autor(es)

Zhou, Yongjun ^[1] ; Murphy, Annabel C. ^[1] ; Samborskyy, Markiyan ^[1] ; Prediger, Patricia ^[2] ; Dias, Luiz Carlos ^[3] ; Leadlay, Peter F. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA - England

^[2] State Univ Campinas UNICAMP, Fac Technol, BR-13484033 Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Inst Chem, UNICAMP, BR-13084971 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CHEMISTRY & BIOLOGY; v. 22, n. 6, p. 745-754, JUN 18 2015.
• Citações Web of Science: 22

Resumo

Conglobatin is an unusual C-2-symmetrical macrodiolide from the bacterium Streptomyces conglobatus with promising antitumor activity. Insights into the genes and enzymes that govern both the assembly-line production of the conglobatin polyketide and its dimerization are essential to allow rational alterations to be made to the conglobatin structure. We have used a rapid, direct in vitro cloning method to obtain the entire cluster on a 41-kbp fragment, encoding a modular polyketide synthase assembly line. The cloned cluster directs conglobatin biosynthesis in a heterologous host strain. Using a model substrate to mimic the conglobatin monomer, we also show that the conglobatin cyclase/thioesterase acts iteratively, ligating two monomers head-to-tail then re-binding the dimer product and cyclizing it. Incubation of two different monomers with the cyclase produces hybrid dimers and trimers, providing the first evidence that conglobatin analogs may in future become accessible through engineering of the polyketide synthase. (AU)

• Processo FAPESP: 12/02230-0 - Síntese total de produtos bioativos: testes biológicos e design de novos análogos estruturais
• Beneficiário: Luiz Carlos Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/04616-3 - Síntese dos compostos de origem marinha ieodomicinas A-D, comosusóis A-D, comosona A e análogos: Estudo da relação estrutura/atividade biológica.
• Beneficiário: Patricia Prediger
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado