期刊
CHEMBIOCHEM
卷 16, 期 18, 页码 2585-2589出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201500496
关键词
acyl-CoA dehydrogenase; biosynthesis; epoxyketones; peptide/polyketide hybrid; proteasome inhibitor
资金
- Pew Scholars Program
- National Institutes of Health [DP2AT009148]
Epoxyketone proteasome inhibitors have attracted much interest due to their potential as anticancer drugs. Although the biosynthetic gene clusters for several peptidyl epoxyketone natural products have recently been identified, the enzymatic logic involved in the formation of the terminal epoxyketone pharmacophore has been relatively unexplored. Here, we report the identification of the minimal set of enzymes from the eponemycin gene cluster necessary for the biosynthesis of novel metabolites containing a terminal epoxyketone pharmacophore in Escherichia coli, a versatile and fast-growing heterologous host. This set of enzymes includes a non-ribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), and an acyl-CoA dehydrogenase (ACAD) homologue. In addition to the in vivo functional reconstitution of these enzymes in E. coli, in vitro studies of the eponemycin NRPS and C-13-labeled precursor feeding experiments were performed to advance the mechanistic understanding of terminal epoxyketone formation.
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