On April 25, Stephen G. Withers the Khorana Professor of Biological Chemistry at the University of British Columbia, guested at the “Inspiring Wisdom” Distinguished Lectures. He delivered a wonderful speech under the title "New access to complex glycoconjugates through engineering and evolution of glycosyltransferases and glycosynthases".

Glycans on the surfaces of cells play key roles in the interaction of that cell with its environment, primarily through interaction with specific protein-based receptors. Study of these interactions requires access to these complex glycans, while interference with these interactions, most likely through the use of competing glycans, is a possible therapeutic approach. Such studies require synthesis of glycans, and on a large scale in the case of therapeutics. Traditional routes to the enzymatic synthesis of oligosaccharides have either involved the use of Nature’s own biosynthetic enzymes, the glycosyl transferases, or glycosidases run in transglycosylation mode. Each approach has its drawbacks. Glycosynthases are mutant glycosidases in which the catalytic nucleophile has been removed. When used in conjunction with glycosyl fluorides of the opposite anomeric configuration to that of the substrate, these enzymes function as highly efficient transferases, frequently giving stoicheometric yields. Thioglycoligases are a new class of mutant glycosidases in which the acid/base catalyst has been mutated. These enzymes synthesise sulfur-linked oligosaccharides when an activated donor is used in conjunction with a thiosugar acceptor. Recent results in the engineering of these two classes of mutant enzymes, as well as of “classical” glycosyl transferases, will be discussed. Particular attention will be paid to their application to oligosaccharides and glycolipids. Emphasis will be placed upon the directed evolution of these enzymes using a variety of screening methodologies including robot-assisted ELISA assays and FACS cell sorting.

Professor Stephen G. Withers obtained his BSc and PhD at the University of Bristol, UK, then moved to Canada in 1977 as a postdoctoral fellow at the University of Alberta. In 1982 he joined the University of British Columbia as assistant professor rising through the ranks to his current position. Professor Withers’ research interests centre on understanding how enzymes that form and degrade glycans work as such incredible catalysts. Using the tools of chemistry, biochemistry and microbiology and many collaborations, his work has led to the uncovering of several `new` mechanisms for glycoside cleavage, the development of new glycosynthases for synthesis, as well as to exciting potential new therapeutics for Influenza, Diabetes and Gaucher disease. His recognitions include the Whistler Award of the International Carbohydrate Organisation (2002) and the Centennial Medal of the Royal Society of Chemistry (2012), as well as Fellowship in the Royal Society of Canada (2007) and the Royal Society of London (2012).