James K. Coward, Ph.D.

 

James K. Coward, Ph.D. is Professor of Medicinal Chemistry and Professor of Chemistry, University of Michigan. He obtained the A.B. degree with a major in chemistry from Middlebury College in 1960, after which he was employed as a chemist by American Cyanamid Co. in Stamford, CT. He returned to school at Duke University, intending to pursue a Ph.D. in physical organic chemistry. Following a stimulating introduction to biochemistry by Prof. Philip Handler, he moved to the State University of New York at Buffalo to study medicinal chemistry with Prof. B. R. Baker (Ph.D., 1967). Postdoctoral research in bioorganic chemistry with Prof. Thomas C. Bruice at the University of California, Santa Barbara, supported by a NIH fellowship, completed his formal education at an exciting time when the fields of medicinal chemistry and mechanistic enzymology could interact in a synergistic manner.

In 1969, Coward joined the faculty of the Department of Pharmacology at Yale University School of Medicine. In 1979, he moved to the Department of Chemistry, Rensselaer Polytechnic Institute and in 1987, accepted his present position at the University of Michigan. Initial research involved mechanistic studies of catechol O-methyltransferase and related model reactions. This research was expanded to include the related alkyl transfer reactions catalyzed by spermidine synthase and spermine synthase, two key steps in polyamine biosynthesis. In addition to steady-state kinetic studies, this research involved the use of chiral methyl and methylene substrates to determine the stereochemistry of enzyme-catalyzed alkyl transfer reactions. First-generation inhibitor synthesis focused on metabolically stable analogs of the products, S-adenosylhomocysteine and methylthioadenosine. Second-generation inhibitor synthesis was aimed at “multisubstrate adduct” inhibitors of catechol O-methyltransferase, spermidine synthase (AdoDATO, AdoSpd), and spermine synthase (AdoDATAD). In related research, a series of α-methyl polyamines, designed to resist oxidative metabolism, proved to be useful for the study of polyamine function in vivo.

The biosynthesis and hydrolysis of poly-γ-glutamate derivatives of reduced folates and antifolates are catalyzed by folylpoly-γ-glutamate synthetase, an ATP-dependent ligase, and γ-glutamyl hydrolase, a cysteine peptidase, respectively. Mechanistic research on the synthetase included demonstration of a transient acyl phosphate intermediate using 17O- and 18O-labeled substrates, and kinetic studies on multiple ligations using substrate trapping and pulse-chase methods. Development of a new fluorescence assay for the hydrolase led to an extensive kinetics analysis of enzyme-catalyzed isopeptide hydrolysis. Based on these mechanistic studies, the design and synthesis of a series of phosphinic acid-containing pseudopeptides resulted in potent and specific inhibitors of the synthetase, and methods for the synthesis of internal epoxide peptidomimetics as potential inhibitors of the hydrolase were developed. Extension of this approach has resulted in the synthesis of aryl phosphinic acids as potential inhibitors of dihydrofolate synthetase, a new target for antimalarial drug design, and alkyl phosphinic acids as potent inhibitors of glutathionylspermidine synthetase, a new target for antitrypanosomal drug design.

In the area of carbohydrate chemistry, the Coward group has investigated several glycosyltransferases, including oligosaccharyltransferase. Use of isotopically labeled peptides and disaccharides, as well as developing an epoxide fluoridolysis method for the synthesis of 5-fluoro 2-amino sugars have provided mechanistic insight and inhibitors for this important group of enzymes.

Coward has served the medicinal chemistry community in a variety of leadership positions. He was a member of the Long Range Planning Committee, ACS Division of Medicinal Chemistry (1989-1991) and Alternate Councilor and member of the Executive Committee, ACS Division of Biological Chemistry as (1991-1993). He has served on the Editorial Boards of Biochemical Pharmacology (1984-1996), Journal of Medicinal Chemistry (1988-1992) and Annual Review of Pharmacology & Toxicology (1997-2002). At the University of Michigan, he was the Program Director of the Chemistry-Biology Interface Training Program (1995-2005) and Principal Investigator of the underlying NIH Training Grant. He was the first Chair of a newly created Department of Medicinal Chemistry at the University of Michigan (1998-2004) and Director of the longstanding Interdepartmental Program in Medicinal Chemistry Program during that period. As a member of NIH study sections (Medicinal Chemistry ‘A’, 1979; Experimental Therapeutics, 1979-1982) and review committees (Pharmacological Sciences Review Committee (1987-1991), and numerous advisory panels (NIH, NSF), he has been an advocate for academic medicinal chemistry research. He has been mentor for over 50 graduate students and postdoctoral associates, as well as over 25 undergraduate students. He is a Fellow, Chemistry Section, American Association for the Advancement of Science (2002).