Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5'''- P1P3-triphosphate hydrolase

Larry D. Barnes, Preston N. Garrison, Zurab Siprashvili, Andrzej Guranowski, Angela K. Robinson, Stephen W. Ingram, Carlo M. Croce, Masataka Ohta, Kay Huebner

Research output: Contribution to journalArticlepeer-review

370 Scopus citations

Abstract

Human Fhit (fragile histidine triad) protein, encoded by the FHIT putative tumor suppressor gene, is a typical dinucleoside 5',5'''-P1,P3- triphosphate (Ap3A) hydrolase (EC 3.6.1.29) on the basis of its enzymatic properties we report here. Ap3A is the preferred substrate among Ap(u)A (n = 3-6), and AMP is always one of the reaction products. Mn2+ and Mg2+ are equally stimulatory, while Zn2+ is inhibitory with Ap3A as the substrate. Values of the K(m) for Ap3A and Ap4A are 1.3 and 4.6 μM, respectively. Values of the specificity constant, k(cat)/K(m) for Ap3A and Ap4A are 2.0 x 106 and 6.7 x 103 s-1 M-1, respectively, for a glutathione S- transferase (GST)-Fhit fusion protein. Site-directed mutagenesis of FHIT demonstrated that all four conserved histidines are required for full activity, and the central histidine of the triad is absolutely essential for Ap3A hydrolase activity. This putative tumor suppressor is the first evidence lot a connection between dinucleotide oligophosphate metabolism and tumorigenesis. Also, Fhit is the first HIT protein in which the histidine residues have been demonstrated by mutagenesis to be critical for function.

Original languageEnglish (US)
Pages (from-to)11529-11535
Number of pages7
JournalBiochemistry
Volume35
Issue number36
DOIs
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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