"Biosynthesis of the Salinosporamide A Polyketide Synthase Substrate Chloroethylmalonyl-Coenzyme A from S-Adenosyl-L-Methionine" by Alessandra S. Eustáquio

Article

Biosynthesis of the Salinosporamide A Polyketide Synthase Substrate Chloroethylmalonyl-Coenzyme A from S-Adenosyl-L-Methionine

Proceedings of the National Academy of Sciences (PNAS) (2009)

Alessandra S. Eustáquio, University of California - San Diego
Ryan P. McGlinchey, University of California - San Diego
Yuan Liu, University of California - San Diego
Chris Hazzard, Portland State University
Laura L. Beer, University of Arizona
Galina Florova, Portland State University
Mamoun M. Alhamadsheh, Portland State University
Anna Lechner, University of California - San Diego
Andrew J. Kale, University of California - San Diego
Yoshihisa Kobayashi, University of California - San Diego
Kevin A. Reynolds, Portland State University
Bradley S. Moore, University of California - San Diego

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Abstract

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′-ClDA) 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′-ClDA 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.

Disciplines

Chemistry

Publication Date

July, 2009

DOI

10.1073/pnas.0901237106

Citation Information

Eustáquio, Alessandra S. et al. “Biosynthesis of the Salinosporamide A Polyketide Synthase Substrate Chloroethylmalonyl-Coenzyme A from S-Adenosyl-L-Methionine.” Proceedings of the National Academy of Sciences of the United States of America 106.30 (2009): 12295–12300. PMC. Web. 27 Jan. 2017.