Characterization of 5-Chloro-5-Deoxy-d-Ribose 1-Dehydrogenase in Chloroethylmalonyl Coenzyme A Biosynthesis

Abstract

SalM is a short-chain dehydrogenase/reductase enzyme from the marine actinomycete Salinispora tropica that is involved in the biosynthesis of chloroethylmalonyl-CoA, a novel halogenated polyketide synthase extender unit of the proteasome inhibitor salinosporamide A. SalM was heterologously overexpressed in Escherichia coli and characterized in vitro for its substrate specificity, kinetics, and reaction profile. A sensitive real-time 13

Identification of a fluorometabolite from Streptomyces sp. MA37: (2R3S4S)-5-fluoro-2,3,4-trihydroxypentanoic acid

“…SalM was found to catalyse the NAD + dependant oxidation of 5-ClR 14 to 5-chlororibolactone 15 , which is then hydrolysed to 5-chlororibonate 16 during studies exploring the biosynthesis of salinosporamide A 11 . 21 …”

Revisiting the methionine salvage pathway and its paralogues

“…This implies formation of 5-deoxy-5-fluoro-ribose, prior to action of a dehydrogenase. Another idea of what could happen can be seen in the catabolism of 5-chloro-5-deoxy-D-ribose in the marine actinomycete Salinispora tropica by a chlorodeoxyribose-1-dehydrogenase producing chloroethylmalonyl-CoA (Kale et al, 2010). Ethylmalonyl-CoA would then enter an acetate pathway as in Methylobacterium extorquens (Schneider et al, 2012).…”

The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery

“…While the C-2 ethyl group in the deschloro-analog originates from butyrate via ethylbutyryl-CoA 69 , the chloroethyl group in salinosporamide A is derived from a new chlorination mechanism driven by the S-adenosyl-L-methionine-dependent chlorinase SalL 70 . The halogenated product 5-chloro-5-deoxyadenosine is then converted in a seven-step route to chloroethylmalonyl-CoA, which acts as an unprecedented halogenated PKS extender unit in salinosporamide A biosynthesis 71, 72 . The biosynthetic pathway to chloroethylmalonyl-CoA is unique to salinosproamide A and has not yet been observed in public DNA sequence databases, thereby supporting the notion that new microbial genera harbor novel biosynthetic processes.…”