Salinosporamide A, a natural product discovered in the marine actinomycete Salinispora tropica, has demonstrated potent inhibition of the 20S proteasome and is currently in clinical trials for anti-cancer therapy.  SalM, a short-chain dehydrogenase/reductase (SDR) enzyme, has been revealed to oxidize 5-chlororibose to 5-chlororibonate en route to chloroethylmalonyl-CoA, a novel PKS extender unit that is incorporated into salinosporamide A.  The biochemistry of SalM has been investigated with in vivo and in vitro experiments.  Alternate substrates and downstream implications have also been explored.  Further characterization of this protein and others in the chloroethylmalonyl-CoA pathway will facilitate the creation of additional polyketide extender units and the introduction of chloroethylmalonyl-CoA into alternative natural product producers.