Probing the Substrate Recognition Mechanism of the Human MTH1 Protein by Nucleotide Analogs

Hiroyuki Kamiya, Hiroyuki Yakushiji, Laurence Dugué, Mitsuhide Tanimoto, Sylvie Pochet, Yusaku Nakabeppu, Hideyoshi Harashima

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

To examine the substrate recognition mechanism of the human MTH1 protein, which hydrolyzes 2-hydroxy-dATP, 8-hydroxy-dATP, and 8-hydroxy-dGTP, ten nucleotide analogs (8-bromo-dATP, 8-bromo-dGTP, deoxyisoinosine triphosphate, 8-hydroxy-dITP, 2-aminopurine-deoxyriboside triphosphate, 2-amino-dATP, deoxyxanthosine triphosphate, deoxyoxanosine triphosphate, dITP, and dUTP) were incubated with the MTH1 protein. Of these, the former five nucleotides were hydrolyzed with various efficiencies. The fact that the syn-oriented brominated nucleotides were hydrolyzed suggests that the MTH1 protein binds to deoxynucleotides adopting the syn-conformation. However, 8-hydroxy-dITP, which lacks the 2-amino group of 8-hydroxy-dGTP, was degraded with tenfold less efficiency as compared with 8-hydroxy-dGTP. In addition, deoxyisoinosine triphosphate, lacking the 6-amino group of 2-hydroxy-dATP, was hydrolyzed as efficiently as 8-hydroxy-dGTP, but less efficiently than 2-hydroxy-dATP. These results clarify the effects of the anti/syn conformation and the functional groups on the 2 and 6 positions of the purine ring on the recognition by the human MTH1 protein.

Original languageEnglish
Pages (from-to)843-850
Number of pages8
JournalJournal of Molecular Biology
Volume336
Issue number4
DOIs
Publication statusPublished - Feb 27 2004

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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