期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 30, 页码 12295-12300出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901237106
关键词
actinomycete; biological halogenation; marine natural product; proteasome inhibitor; Salinispora tropica
资金
- Life Sciences Research Foundation
- National Sea Grant-Industry Graduate Fellow through the Washington Sea [R/B-47]
- National Oceanic and Atmospheric Administration [NA05NOS4781249]
- National Institutes of Health [CA127622, AI51629]
Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway to chloroethylmalonyl-CoA as a polyketide synthase building block in the biosynthesis of salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity. S-adenosyl-L-methionine (SAM) is converted to 5'-chloro-5'-deoxyadenosine (5'-CIDA) in a reaction catalyzed by a SAM-dependent chlorinase as previously reported. By using a combination of gene deletions, biochemical analyses, and chemical complementation experiments with putative intermediates, we now provide evidence that 5'-CIDA is converted to chloroethylmalonyl-CoA in a 7-step route via the penultimate intermediate 4-chlorocrotonyl-CoA. Because halogenation often increases the bioactivity of drugs, the availability of a halogenated polyketide building block may be useful in molecular engineering approaches toward polyketide scaffolds.
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