Document Report Card

ID: ALA1121725

Journal: J Med Chem

Title: Interaction of 1-(5-phospho-beta-D-arabinofuranosyl)-5-substituted-uracils with thymidylate synthetase: mechanism-based inhibition by 1-(5-phospho-beta-D-arabinosyl)-5-fluorouracil.

Authors: Nakayama C, Wataya Y, Santi DV, Saneyoshi M, Ueda T.

Abstract: A number of 1-(5-phospho-beta-D-arabinosyl)-5-substituted-uracils (ara-UMP's) have been examined as inhibitors of dTMP synthetase. As reversible inhibitors, all were substantially less potent than their 2'-deoxyribosyl counterparts. In the presence of 5,10-methylenetetrahydrofolate (CH2-H4folate), ara-FUMP caused a first-order, time-dependent inactivation of the enzyme. At 0 degrees C, kinetic studies indicated a reversible Kd of 3.6 micro M for the ara-FUMP-CH2-H4folate complex, and k = 0.22 min-1 for the subsequent inactivation. Spectral studies of the complex and its behavior toward protein denaturants demonstrate that its structure and stoichiometry are directly analogous to those which have previously been described for FdUMP. The significance of this finding with regard to prodrugs of ara-FU and the potential of ara-FU as a chemotherapeutic agent are discussed.

CiteXplore: 7328576

DOI: 10.1021/jm00142a008