Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors

Metalloproteinase inhibitors are leads for drug development, but their biosynthetic pathways are often unknown. Here the authors show that the acyl branched warhead of actinonin and matlystatins derives from an ethylmalonyl-CoA-like pathway and the structural diversity of matlystatins is due to the activity of a decarboxylase-dehydrogenase enzyme.