Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine.
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.
Eustáquio
Alessandra S
AS
Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0204, USA.
McGlinchey
Ryan P
RP
Liu
Yuan
Y
Hazzard
Christopher
C
Beer
Laura L
LL
Florova
Galina
G
Alhamadsheh
Mamoun M
MM
Lechner
Anna
A
Kale
Andrew J
AJ
Kobayashi
Yoshihisa
Y
Reynolds
Kevin A
KA
Moore
Bradley S
BS
D001426:Bacterial Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017338:Cladribine / Q000737:chemistry / Q000378:metabolism*; D003001:Cloning, Molecular; D023061:Gene Order; D016680:Genome, Bacterial / Q000235:genetics; D007700:Kinetics; D007783:Lactones / Q000737:chemistry / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008848:Micromonosporaceae / Q000235:genetics / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D009154:Mutation; D010802:Phylogeny; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013379:Substrate Specificity
D001426:Bacterial Proteins; D007783:Lactones; D011758:Pyrroles; D017338:Cladribine; D008316:Malonyl Coenzyme A; C475865:marizomib; D048630:Polyketide Synthases; D012436:S-Adenosylmethionine; C044739:5'-chloro-5'-deoxyadenosine