Insight into the Chemical Mechanism of Thymidylate Synthase-Catalyzed Reaction Through the Evaluation of Chemical Models: The Role of C6 Sulfhydryl Addition During the Reductive Elimination Step of the Reaction1

✍ Scribed by B.H. Wang; J.R. Kagel; M.P. Mertes; K. Bowmanjames

• Book ID: 102966046
• Publisher: Elsevier Science
• Year: 1994
• Tongue: English
• Weight: 795 KB
• Volume: 22
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1006/bioo.1994.1034

✦ Synopsis

Thymidylate synthase catalyzes the last step of the de novo synthesis of thymidine-5'monophosphate (TMP), which has long been a target for the development of effective anticancer agents. Model compounds ((15,16,17)) were used to study the effect of (\mathrm{C6}) nucleophilic addition on the reductive elimination step of the TS-catalyzed reaction. Results suggest that (\mathrm{C} 6) addition facilitates the reductive elimination of the (\mathrm{H}_{2}) folate moiety of the ternary intermediate (3). Therefore, the reaction pathway (pathway (b)) with the participation of C6 sulfhydryl addition during the reductive elimination process is the energetically favored process. Consequently, the elimination of the cysteine sulfhydryl group from the (\mathrm{C} 6) position is the last step of the reaction before the dissociation of the products from the enzyme. D 1994 Academic Press, Inc.