marizomib and 5--chloro-5--deoxyadenosine

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.

Topics: Bacterial Proteins; Chromatography, High Pressure Liquid; Cladribine; Cloning, Molecular; Gene Order; Genome, Bacterial; Kinetics; Lactones; Malonyl Coenzyme A; Micromonosporaceae; Models, Chemical; Molecular Sequence Data; Molecular Structure; Multigene Family; Mutation; Phylogeny; Polyketide Synthases; Pyrroles; S-Adenosylmethionine; Sequence Analysis, DNA; Substrate Specificity