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Research ArticleArticle

Fluorinated Pyrimidines XXVI. Mammalian Thymidylate Synthetase: Its Mechanism of Action and Inhibition by Fluorinated Nucleotides

PHILIP REYES and CHARLES HEIDELBERGER
Molecular Pharmacology July 1965, 1 (1) 14-30;
PHILIP REYES
McArdle Laboratory, The Medical School, University of Wisconsin, Madison, Wisconsin
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CHARLES HEIDELBERGER
McArdle Laboratory, The Medical School, University of Wisconsin, Madison, Wisconsin
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Abstract

Thymidylate synthetase from Ehrlich ascites carcinomna cells has been assayed by a spectrophotometric method, and several new properties of this enzyme have been discovered. Thymidylate produces a weak noncompetitive product inhibition and mercaptoethanol stimulates the enzyme activity, whereas formaldehyde must be present within a specific concentration range if maximal enzyme activity is to occur. In addition, the results of initial velocity and product-inhibition kinetic studies as well as those of experiments designed to study the kinetics of the inhibition produced by 5-fluoro-2'-deoxyuridine 5'-monophosphate and 5-trifluoromethyl-2'-deoxyuridine 5'-monophosphate made it possible to elucidate the mechanism of action of thymidylate synthetase. The mechanism is ordered and sequential, such that 5,10-methylenetetrahydrofolate interacts with the enzyme before deoxyuridylate, and thymidylate leaves before dihydrofolate. Furthermore, a mechanism without central complexes has been eliminated. 5-Trifluoromethyl-2'-deoxyuridine 5'-monophosphate, unlike 5-fluoro-2'-deoxyuridine 5'-monophosphate, exhibits the ability to combine slowly with the enzyme in an irreversible fashion.

ACKNOWLEDGMENT The authors would like to thank Professor W. W. Cleland for several valuable and helpful discussions during the course of this investigation. This work was supported in part by grants CRTY-5002 and CA-07175 from the National Cancer Institute, United States Public Health Service, Bethesda, Maryland.

  • Copyright ©, 1965, by Academic Press Inc.

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Molecular Pharmacology
Vol. 1, Issue 1
1 Jul 1965
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Research ArticleArticle

Fluorinated Pyrimidines XXVI. Mammalian Thymidylate Synthetase: Its Mechanism of Action and Inhibition by Fluorinated Nucleotides

PHILIP REYES and CHARLES HEIDELBERGER
Molecular Pharmacology July 1, 1965, 1 (1) 14-30;

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Research ArticleArticle

Fluorinated Pyrimidines XXVI. Mammalian Thymidylate Synthetase: Its Mechanism of Action and Inhibition by Fluorinated Nucleotides

PHILIP REYES and CHARLES HEIDELBERGER
Molecular Pharmacology July 1, 1965, 1 (1) 14-30;
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