Investigating the biosynthesis of chloroethylmalonyl-CoA: a building block of salinosporamide A

           Salinosporamide A, a highly bioactive b-lactone from the marine bacterium Salinispora tropica, originates from three biosynthetic building blocks, namely acetate (green), 4-chlorobutyric acid (red) and the non-proteinogenic amino acid b-hydroxy-3-cyclohexenylalanine (blue). The unexpected and unprecedented chlorination pathway of chloroethylmalonyl-CoA was illuminated by a multidisciplinary approach involving genetics, organic synthesis and protein biochemistry, where S-adenosyl-L-methionine (SAM) is converted to chloroethylmalonyl-CoA in a series of reactions catalyzed by pathway-specific enzymes evolved from primary metabolic homologs. The elucidation of the biosynthetic pathway to this novel PKS extender unit affords ready access to new fermentation-based salinosporamide A variants for SAR studies through rational metabolic engineering.