Structural Development of Enzymes Toolbox for Natural Product Biosynthesis

Abstract

Natural products, known as chemical compounds or substances produced by living organisms, are arguably the most important in revolutionizing modern medicine: penicillin, the aminoglycosides, cephalosporins, tetracyclins and others. To date, natural products remain the best source of drug leads with greater than 50% of the new chemical entities reported since 1981 being derived from natural products. However, one of the shortcomings of natural product‐based drug discovery is the difficulty in structural derivatization. The traditional chemical modification methods remain problematic due to the large variety of functional groups often require multiple protection and deprotection steps, making the process quite difficult and laborious. To help with this, we are trying to make natural product derivatives from enzymatic way. Jon Thorson lab in University of Kentucky has amassed an impressive array of tools and expertise toward understanding and exploiting natural product biosynthesis. Our lab collaborate with them to solve the X‐ray structures of the high‐value, feasible enzyme targets and further engineer them to produce new biosynthetic natural products derivatives. Herein I present structural studies of three parts of our natural product biosynthesis enzymes toolbox: (1) methyltransferases (MTs) and methionine adenosyltransferases (MATs); (2) glycosyltransferase (GTs); (3) sugar aminotransferase.