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| http://purl.uniprot.org/citations/21222488 | http://www.w3.org/2000/01/rdf-schema#comment | "Human thymidine phosphorylase (hTP) is responsible for thymidine (dT) homeostasis, promotes angiogenesis, and is involved in metabolic inactivation of antiproliferative agents that inhibit thymidylate synthase. Understanding its transition state structure is on the path to design transition state analogues. Arsenolysis of dT by hTP permits kinetic isotope effect (KIE) analysis of the reaction by forming thymine and the chemically unstable 2-deoxyribose 1-arsenate. The transition state for the arsenolytic reaction was characterized using multiple KIEs and computational analysis. Transition state analysis revealed a concerted bimolecular (A(N)D(N)) mechanism. A transition state constrained to match the intrinsic KIE values was found using density functional theory (B3LYP/6-31G*). An active site histidine is implicated as the catalytic base responsible for activation of the arsenate nucleophile and stabilization of the thymine leaving group during the isotopically sensitive step. At the transition state, the deoxyribose ring exhibits significant oxocarbenium ion character with bond breaking (r(C-N) = 2.45 Å) nearly complete and minimal bond making to the attacking nucleophile (r(C-O) = 2.95 Å). The transition state model predicts a deoxyribose conformation with a 2'-endo ring geometry. Transition state structure for the slow hydrolytic reaction of hTP involves a stepwise mechanism [Schwartz, P. A., Vetticatt, M. J., and Schramm, V. L. (2010) J. Am. Chem. Soc. 132, 13425-13433], in contrast to the concerted mechanism described here for arsenolysis."xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.org/dc/terms/identifier | "doi:10.1021/bi101900b"xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/author | "Schramm V.L."xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/author | "Schwartz P.A."xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/author | "Vetticatt M.J."xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/name | "Biochemistry"xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/pages | "1412-1420"xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/title | "Transition state analysis of the arsenolytic depyrimidination of thymidine by human thymidine phosphorylase."xsd:string |
| http://purl.uniprot.org/citations/21222488 | http://purl.uniprot.org/core/volume | "50"xsd:string |
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