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Type: Artigo de periódico
Title: Iterative Mechanism Of Macrodiolide Formation In The Anticancer Compound Conglobatin
Author: Zhou
Yongjun; Murphy
Annabel C.; Samborskyy
Markiyan; Prediger
Patricia; Dias
Luiz Carlos; Leadlay
Peter F.
Abstract: 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.
Subject: Modular Polyketide Synthases
Streptomyces Sp
Cellulose Biosynthesis
Thioesterase Domain
Sequence Motifs
Citation: Iterative Mechanism Of Macrodiolide Formation In The Anticancer Compound Conglobatin. Cell Press, v. 22, p. 745-754 Jun-2015.
Rights: fechado
Identifier DOI: 10.1016/j.chembiol.2015.05.010
Date Issue: 2015
Appears in Collections:Unicamp - Artigos e Outros Documentos

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