In order to establish a base of structural knowledge concerning structure, function, and regulation in the enigmatic family of manganese metalloenzymes, we have selected the metallohydrolase rat liver arginase as the paradigm for protein engineering and rational ligand design experiments. This enzyme is extraordinary in that it contains a binuclear, spin-coupled manganese cluster in its active site that is implicated in the chemistry of ariginine hydrolysis. In addition to yielding the first structure of a mammalian urea cycle enzyme (where cytosolic arginase catalyzes the hydrolysis of arginine into omithine plus urea), our structural studies of arginase complement studies of its role in nitric oxide (NO) biology. The activities of nitric oxide synthase and arginase in various tissues are reciprocally coordinated in order to modulate NO-dependent processes. In this role, we have implicated arginase as a potential target for therapeutic intervention in the treatment of erectile dysfunction. We have achieved key goals outlined in the original grant proposal, and we now request continued support for X-ray crystallographic studies of arginase, its site-specific variants, and its inhibitor complexes. Additionally, building on our successful design and evaluation of potent boromc acid-based arginase inhibitors in the current funding period, we request support for exploring the development of new inhibitors in a structure-based design approach. New inhibitor designs may exhibit enhanced properties such as affinity and membrane permeability, which may facilitate physiological studies of arginase inhibition in the laboratories of our collaborators.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049758-11
Application #
6837196
Study Section
Special Emphasis Panel (ZRG1-PC (01))
Program Officer
Basavappa, Ravi
Project Start
1994-05-01
Project End
2006-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
11
Fiscal Year
2005
Total Cost
$235,581
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Porter, Nicholas J; Wagner, Florence F; Christianson, David W (2018) Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6. Biochemistry 57:3916-3924
Bhatia, Sanil; Krieger, Viktoria; Groll, Michael et al. (2018) Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor. J Med Chem 61:10299-10309
Porter, Nicholas J; Osko, Jeremy D; Diedrich, Daniela et al. (2018) Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity. J Med Chem 61:8054-8060
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Shinsky, Stephen A; Christianson, David W (2018) Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10. Biochemistry 57:3105-3114
Porter, Nicholas J; Mahendran, Adaickapillai; Breslow, Ronald et al. (2017) Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc Natl Acad Sci U S A 114:13459-13464
Hai, Yang; Shinsky, Stephen A; Porter, Nicholas J et al. (2017) Histone deacetylase 10 structure and molecular function as a polyamine deacetylase. Nat Commun 8:15368
Bitler, Benjamin G; Wu, Shuai; Park, Pyoung Hwa et al. (2017) ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19:962-973
Porter, Nicholas J; Christianson, David W (2017) Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8. ACS Chem Biol 12:2281-2286
Gantt, Sister M Lucy; Decroos, Christophe; Lee, Matthew S et al. (2016) General Base-General Acid Catalysis in Human Histone Deacetylase 8. Biochemistry 55:820-32

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