Progress in combinatorial biosynthesis for drug discovery.

Combinatorial biosynthesis, the process of genetic manipulations of natural product biosynthetic machinery for structural diversity, depends on several factors, and discussed here are two critical factors: access to genetic information and biochemical characterization of enzymes. Examples of the former include using predictions for the biosynthesis of unusual chemical entities such as aminohydroxybenzoic acid starter units, methoxymalonylate extender units, the enediyne core and bacterial aromatic polyketides. The latter aspect includes the continued elucidation of domain functionalities of modular polyketide synthases and nonribosomal peptide synthases and novel biochemical pathways such as the biosynthesis of a cyclopropyl unit and a β-hydroxyl acid. Finally, examples of successful combinatorial biosynthesis for daptomycin and indolocarbozole compounds are discussed.: © Published by Elsevier Ltd.