faculty

Professor of Medicinal Chemistry and Chemistry
Ph.D., State University of New York-Buffalo

Bioorganic and Medicinal Chemistry. Organic Chemistry Related to Biological Reactions; Mechanism of Enzyme-Catalyzed Reactions. Synthesis and Enzymology of Mechanism-Based Enzyme Inhibitors

Phone: (734) 936-2843
E-mail: jkcoward@umich.edu
Fax: (734) 647-4865

Research Group

Research in our laboratory involves synthetic and mechanistic organic chemistry employed in combination with mechanistic biochemistry. Our ultimate goal is to design potent and specific "mechanism-based inhibitors" of selected target enzymes for use as drugs in the treatment of cancer and parasitic diseases. Three different types of enzymes have been selected for study: folylpolyglutamate synthetase/ gamma-glutamyl hydrolase, glutathionylspermidine synthetase/amidase, and oligosaccharyltransferase.

Folic acid is a key vitamin in human nutrition. Cellular folates contain a reduced pteridine heterocycle and a poly gamma-glutamyl peptide "tail." Two enzymes, folylpolyglutatmate synthetase (FPGS) and gamma-glutamyl hydrolase (GH), being studied by our research group, catalyze the biosynthesis and hydrolytic cleavage, respectively, of the polyglutamyl portion of cellular folates and antifolate drugs. Recent research has involved the synthesis of several fluoro- and phosphoamino acids and their incorporation into folates and antifolate drugs. These efforts have led to the synthesis of fluoropeptides and phosphapeptides for biochemical investigation as inhibitors or stimulators of the reactions catalyzed by FPGS or GH. In collaborative research, our new compounds are being used in intact mammalian cells to assess the role of polyglutamate formation and hydrolysis in normal folate-dependent one-carbon biochemistry and also in the pharmacology of antifolate drugs used in the treatment of cancer.

Trypanothione (TSH), found exclusively in trypanosomatid parasites, is a derivative of the ubiquitous antioxidant, glutathione (GSH). We have extended our phosphapeptide research mentioned above to the development of new inhibitors of TSH biosynthesis as possible anti-trypanosomal drugs. Based on an understanding of the mechanism of a key TSH biosynthetic enzyme, we have designed and synthesized specific phosphapeptide inhibitors of the synthetase domain and, in collaborative research have used these compounds to study the regulation of catalysis by this bifunctional enzyme.

Oligosaccharyltransferase (OST), an enzyme that catalyzes the N-glycosylation of proteins, is a membrane-bound protein comprised of nine subunits that we isolate from yeast. Current research involves the synthesis and biochemical study of peptide-based photoinactivators to identify the active site subunit, fluorosugars as potential OST inhibitors, and isotopically labeled disaccharide donors designed to answer specific mechanistic questions. As in the research with folate polyglutamates and trypanothione, the goal is to understand the mechanism of the OST-catalyzed reaction in sufficient detail to design and synthesize potent and specific inhibitors for use in the study of cellular glycoprotein biosynthesis.

AWARDS

• Hall of Fame, Division of Medicinal Chemistry, American Chemical Society, 2007.
• American Association for the Advancement of Science, Fellow
• American Cancer Society Scholar in Cancer Research
• National Institutes of Health Postdoctoral Fellow
  

REPRESENTATIVE PUBLICATIONS

1. Y. Feng and J.K. Coward. Prodrug Forms of N -[(4-deoxy-4-amino-10-methyl)pteroyl]-glutamate -γ -[ ψ P(O)(OH)]-glutarate, a Potent Inhibitor for Folylpoly- γ -glutamate Synthetase: Synthesis and Hydrolytic Stability. J. Med. Chem. 2006 , 49 , 770-788.
   
   
2. C.-H. Pai, B.-Y. Chiang, T.-Z. Ko, C.-C. Chou, C.-M. Chong, F.-J. Yen, S. Chen, J. K. Coward, A. H-J. Wang and C.-H. Lin. Dual Binding Sites for Translocation Catalysis by E. coli Glutathionylspermidine Synthetase. EMBO J. 2006 , 25 , 5970-5982.
   
   
3. Y. Yang and J.K. Coward. Synthesis of p -Aminophenyl Aryl H-Phosphinic Acids and Esters via Cross-Coupling Reactions: Elaboration to Phosphinic Acid Pseudopeptide Analogs of Pteroyl Glutamic Acid and Related Antifolates. J. Org. Chem. , 2007 , 72 , 5748-5758.
   
   
4. M.C.T. Hartman, S. Jiang, J.S. Rush, C.J. Waechter, and J. K. Coward. Glycosyltransferase Mechanisms: Impact of a 5-Fluoro Substituent in Acceptor and Donor Substrates on Catalysis. Biochemistry, 2007 , 46 , 11630-11638.
   
   
5. J.P. Alexander, T.J. Ryan, D.P. Ballou, and J.K. Coward. γ -Glutamyl Hydrolase: Kinetic Characterization of Isopeptide Hydrolysis Using Fluorogenic Substrates. Biochemistry, 2008, 47, 1228-1239.
   
   
6. J.W. Tomsho, R.G. Moran, and J.K. Coward. Concentration-dependent Processivity of Multiple Glutamate Ligations Catalyzed by Folylpoly-γ-glutamate Synthetase. Biochemistry, 2008, 47, 9040-9050.