INSIGHT INTO THE CHEMICAL MECHANISM OF THYMIDYLATE SYNTHASE-CATALYZEDREACTION THROUGH THE EVALUATION OF CHEMICAL-MODELS - THE ROLE OF C6 SULFHYDRYL ADDITION DURING THE REDUCTIVE ELIMINATION STEP OF THE REACTION

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, 1 6, 17) were used to study the effect of C6 nucleophilic addition on th e reductive elimination step of the TS-catalyzed reaction. Results sug gest that C6 addition facilitates the reductive elimination of the H(2 )folate moiety of the ternary intermediate (3). Therefore, the reactio n pathway (pathway (b)) with the participation of C6 sulfhydryl additi on during the reductive elimination process is the energetically favor ed process. Consequently, the elimination of the cysteine sulfhydryl g roup from the C6 position is the last step of the reaction before the dissociation of the products from the enzyme. (C) 1994 Academic Press, Inc.