Abstract

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.

  Funding Agency

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

  Institution

Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Fujinaga, M; Cherney, M M; Tarasova, N I et al. (2000) Structural study of the complex between human pepsin and a phosphorus-containing peptidic -transition-state analog. Acta Crystallogr D Biol Crystallogr 56:272-9
Fraser, M E; Strynadka, N C; Bartlett, P A et al. (1992) Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues. Biochemistry 31:5201-14
Phillips, M A; Kaplan, A P; Rutter, W J et al. (1992) Transition-state characterization: a new approach combining inhibitor analogues and variation in enzyme structure. Biochemistry 31:959-63
Sampson, N S; Bartlett, P A (1991) Peptidic phosphonylating agents as irreversible inhibitors of serine proteases and models of the tetrahedral intermediates. Biochemistry 30:2255-63
Kaplan, A P; Bartlett, P A (1991) Synthesis and evaluation of an inhibitor of carboxypeptidase A with a Ki value in the femtomolar range. Biochemistry 30:8165-70
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
Hanson, J E; Kaplan, A P; Bartlett, P A (1989) Phosphonate analogues of carboxypeptidase A substrates are potent transition-state analogue inhibitors. Biochemistry 28:6294-305
Giannousis, P P; Bartlett, P A (1987) Phosphorus amino acid analogues as inhibitors of leucine aminopeptidase. J Med Chem 30:1603-9
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

Showing the most recent 10 out of 12 publications