Characterization of the Pradimicin A Biosynthetic Pathway

Pradimicin A is a potent antifungal agent and HIV entry inhibitor. Its biosynthetic pathway has been partially characterized and further research may reveal ways to improve its bioactivity. Pradimicin works against pathogens through an interaction of D-xylose, OH-14C, carboxyl group, and D-alanine moieties in pradimicin with D-mannopyranosides found in the pathogen. Prior identification of the functions of tailoring enzymes in pradimicin biosynthesis has been accomplished through combinatorial biosynthesis and gene knockouts. In this research, we have obtained five new pradimicin biosynthetic intermediates, pKN92, KN90, KN87, KN85 and KN82. These intermediates confirm, for the first time, the function of the genes pdmW, pdmS, and pdmT and reveal the order of five important tailoring reactions in the pradimicin biosynthetic pathway. This work allows us to understand pradimicin biosynthesis and further engineer the biosynthesis of new pradimcin analogs with improved therapeutic characteristics.