title: Dimeric dUTPases, HisE, and MazG belong to a new superfamily of all-alpha NTP pyrophosphohydrolases with potential "house-cleaning" functions.
abstract: Structure-guided analysis of the new dimeric dUTPase family revealed its sequence relationship to the phage T4 dCTPase, phosphoribosyl-ATP pyrophosphatase HisE, NTP pyrophosphatase MazG, and several uncharacterized protein families, including the human protein XTP3TPA (RS21-C6), which is overexpressed in embryonic and cancer cells. Comparison with the recently determined structure of a MazG-like protein from Sulfolobus solfataricus supported the unification of these enzymes in one superfamily of all-alpha NTP pyrophosphatases, suggesting that dimeric dUTPases evolved from a tetrameric MazG-like ancestor by gene duplication. Analysis of the structure of the Sulfolobus MazG points to 2-hydroxyadenosine (isoguanosine) triphosphate, a product of oxidative damage of ATP, as the most likely substrate. We predict that uncharacterized members of this superfamily perform "house-cleaning" functions by hydrolyzing abnormal NTPs and are functionally analogous to the structurally unrelated hydrolases of the Nudix superfamily. We outline probable tertiary and quaternary structures of the all-alpha NTP pyrophosphatase superfamily members.
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Moroz
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Murzin
authors.forename: Kira S
authors.initials: KS
authors.lastname: Makarova
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Koonin
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Galperin
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D048229:Sulfolobus solfataricus / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D021122:Protein Subunits; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; C064815:phosphoribosyl-ATP pyrophosphatase; C021895:nucleoside triphosphate pyrophosphatase