The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism |
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Authors: | Harsh V Jain Roshni Rasheed Thomas I Kalman |
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Institution: | 1. Department of Chemistry, University at Buffalo, Buffalo, NY 14260, United States;2. Department of Pharmacology & Toxicology, University at Buffalo, Buffalo, NY 14260, United States |
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Abstract: | The design and synthesis of 5-fluoro-6-(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions. |
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