Three enzymes which are involved in the metabolism of the nucleoside bases will be the targets of inhibitor studies: cytidine deaminase, adenosine deaminase, and carbamyl phosphate synthetase II. With cytidine deaminase, we will investigate the kinetics and mode of inhibition of our phosphorus-containing pyrimidine transition state analog, which we have already demonstrated to be the most potent inhibitor known for this enzyme. For application to adenosine deaminase, the analogous phosphorus-containing purine derivatives will be evaluated. A series of multi-substrate analogs for carbamyl phosphate synthetase will be studied. The deaminase inhibitors may shed light on the mechanism of action of these enzymes, as well as act in a synergistic manner with a number of clinically important anti-neoplastic agents. Selective inhibitors of carbamyl phosphate synthetase could prove to have useful anti-cancer activity in their own right.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022747-08
Application #
3165890
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1978-04-01
Project End
1986-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
8
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Copie, V; Kolbert, A C; Drewry, D H et al. (1990) Inhibition of thermolysin by phosphonamidate transition-state analogues: measurement of 31P-15N bond lengths and chemical shifts in two enzyme-inhibitor complexes by solid-state nuclear magnetic resonance. Biochemistry 29:9176-84
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Bartlett, P A; Marlowe, C K; Giannousis, P P et al. (1987) Phosphorus-containing peptide analogs as peptidase inhibitors. Cold Spring Harb Symp Quant Biol 52:83-90
Mookhtiar, K A; Marlowe, C K; Bartlett, P A et al. (1987) Phosphonamidate inhibitors of human neutrophil collagenase. Biochemistry 26:1962-5

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