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David Ash
Ph.D., Biophysics, University of Pennsylvania, 1983
B.Sc.,Chemistry, Pennsylvania State University, 1974
Office:
Dow 268
Phone:
(989) 774 - 3981
Fax:
(989) 774 - 3883
E-mail:
ash1de@cmich.edu
Research Interests
Ribbon plot of the rat liver arginase structure; the Mn 2+-Mn 2+ cluster in the active sites of each monomer is represented by a pair of spheres.
Research in this laboratory focuses on structure-function-activity relationships for enzymes in involved in arginine metabolism. Arginase is a manganoprotein that catalyzes the hydrolysis of L-arginine to form L-ornithine and urea. Rat liver (cytosolic) and human kidney (mitochondrial) isozymes have been expressed in and purified from E. coli. Crystal structures for both isozymes have been determined. Inhibitor studies have shown that extra-hepatic arginases play a role in regulating nitric oxide production in both male and female sexual organs. Current studies focus on the role of individual amino acids in the catalytic cycle as probed by site-directed mutagenesis.
Manganese coordination interactions.
Peptidylarginine deiminases (PADs) catalyze the conversion of peptidylarginine residues to peptidylcitrulline residues and ammonia. Although the preponderance of PADs are eukaryotic, Ca2+-activated enzymes, a PAD from the prokaryote P. gingivalis, the organism responsible for periodontal disease, has been identified. This PAD has been cloned and expressed in E. coli. Current efforts are focused on characterization of this activity with the ultimate goal of developing potent inhibitors of this enzyme.
Selected Publications
Expression, Purification, and Characterization of Human Type II Arginase. D.M. Colleluori, S.J. Morris, Jr., and D.E. Ash. Arch. Biochem. Biophys. 389, 135-143 (2001).
Classical and Slow-Binding Inhibitors of Human Type II Arginase. D.M. Colleluori and D.E. Ash. Biochemistry 40, 9356-9362 (2001).
Functional Consequences of the G235R Mutation in Liver Arginase Leading to Hyperargininemia. L.T. Lavulo, F.A. Emig and D.E. Ash. Arch. Biochem. Biophys. 399, 49-55 (2002).
Structure and Functional Importance of First-Shell Metal Ligands in the Binuclear Manganese Cluster of Arginase I. E. Cama, F.A. Emig, D.E. Ash, and D.W. Christianson. Biochemistry 42, 7748-7758 (2003).
Human Arginase II: Crystal Structure and Physiological Role in Male and Female Sexual Arousal. E. Cama, D.M. Colleluori, F.A. Emig, H. Shin, S.W. Kim, N.N. Kim, A.M. Traish, D.E. Ash and D.W. Christianson. Biochemistry 42, 8445-8451 (2003).
Inhibitor Coordination Interactions in the Binuclear Manganese Cluster of Arginase. E. Cama, S. Pethe, J.L. Boucher, S. Han, F.A. Emig, D.E. Ash, R.E. Viola, D. Mansuy and D.W. Christianson. Biochemistry 43, 8987-8999 (2004).
Structure and Function of Arginases. D.E. Ash. J. Nutr. 134(10 Suppl), 2760-2764 (2004).
Probing the Role of the Hyper-Reactive Histidine Residue of Arginase. D.M. Colleluori, R.S. Reczkowski, F.A. Emig, E. Cama, J.D. Cox, L.R. Scolnick, K. Compher, K. Jude, S. Han, R.E. Viola, D.W. Christianson, and D.E. Ash. Arch. Biochem. Biophys. 444, 15-26 (2005).
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