Oxidized purine nucleoside triphosphate hydrolase

Definition:

Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool. Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP. Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP. Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A. Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA. Through this antimutagenic activity protects cells from oxidative stress.

References:

[1]. Yasunari Sakai, et al. The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. J Mol Med (Berl). 2006 Aug;84(8):660-70. [Content Brief]

[2]. J Willem M Nissink, et al. MTH1 Substrate Recognition--An Example of Specific Promiscuity. PLoS One. 2016 Mar 21;11(3):e0151154. [Content Brief]

[3]. Helge Gad, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21. [Content Brief]

[4]. Emma Rose Scaletti, et al. MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. J Biol Chem. 2020 Apr 10;295(15):4761-4772. [Content Brief]

[5]. K Fujikawa, et al. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res. 2001 Jan 15;29(2):449-54. [Content Brief]

[6]. Kilian V M Huber, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. 2014 Apr 10;508(7495):222-7. [Content Brief]

[7]. K Fujikawa, et al. The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem. 1999 Jun 25;274(26):18201-5. [Content Brief]

[8]. Ann-Sofie Jemth, et al. MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. Nucleic Acids Res. 2018 Nov 16;46(20):10888-10904. [Content Brief]

[9]. Megan Carter, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nat Commun. 2015 Aug 4;6:7871. [Content Brief]

[10]. Yasunari Sakai, et al. A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. J Biol Chem. 2002 Mar 8;277(10):8579-87. [Content Brief]

[11]. Daisuke Yoshimura, et al. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem. 2003 Sep 26;278(39):37965-73. [Content Brief]

[12]. Y Fujii, et al. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. J Biol Chem. 1999 Dec 31;274(53):38251-9. [Content Brief]

[13]. Manuel Ellermann, et al. Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target. ACS Chem Biol. 2017 Aug 18;12(8):1986-1992. [Content Brief]

[14]. K Sakumi, et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem. 1993 Nov 5;268(31):23524-30. [Content Brief]

[15]. Shaimaa Waz, et al. Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity. J Biol Chem. 2017 Feb 17;292(7):2785-2794. [Content Brief]

[16]. M Furuichi, et al. Genomic structure and chromosome location of the human mutT homologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:G transversion. Genomics. 1994 Dec;24(3):485-90. [Content Brief]

[17]. Yasumitsu Takagi, et al. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012 Jun 15;287(25):21541-9. [Content Brief]

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