ArticleProceedings of the National Academy of Sciences of the United States of America2011
Nucleotide pyrophosphatase employs a P-loop-like motif to enhance catalytic power and NDP/NTP discrimination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 33 citations in OpenAlex.
- dUTPase modulates mycobacterial homologous recombination and interacts with the AdnAB helicase-nuclease.Nucleic acids research · 2026Article
- ROS-Induced DCTPP1 Upregulation Contributes to Cisplatin Resistance in Ovarian Cancer.Frontiers in molecular biosciences · 2022Article
- Identification and Characterization of a Novel Epitope of ASFV-Encoded dUTPase by Monoclonal Antibodies.Viruses · 2021Article
- Redox status of cysteines does not alter functional properties of human dUTPase but the Y54C mutation involved in monogenic diabetes decreases protein stability.Scientific reports · 2021Article
- Beyond Chelation: EDTA Tightly Binds Taq DNA Polymerase, MutT and dUTPase and Directly Inhibits dNTPase Activity.Biomolecules · 2019Article
- The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature.Nature communications · 2019Article
- Article
- Structural model of human dUTPase in complex with a novel proteinaceous inhibitor.Scientific reports · 2018Article
- The dUTPase of white spot syndrome virus assembles its active sites in a noncanonical manner.The Journal of biological chemistry · 2018Article
- Convergent evolution involving dimeric and trimeric dUTPases in pathogenicity island mobilization.PLoS pathogens · 2017Article
- Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes.Scientific reports · 2017Article
- A Hidden Active Site in the Potential Drug Target Mycobacterium tuberculosis dUTPase Is Accessible through Small Amplitude Protein Conformational Changes.The Journal of biological chemistry · 2016Article
- Another look at the mechanism involving trimeric dUTPases in Staphylococcus aureus pathogenicity island induction involves novel players in the party.Nucleic acids research · 2016Article
- Trading in cooperativity for specificity to maintain uracil-free DNA.Scientific reports · 2016Article
- Highly potent dUTPase inhibition by a bacterial repressor protein reveals a novel mechanism for gene expression control.Nucleic acids research · 2014Article
- Catalytic mechanism of α-phosphate attack in dUTPase is revealed by X-ray crystallographic snapshots of distinct intermediates, 31P-NMR spectroscopy and reaction path modelling.Nucleic acids research · 2013Article
- The dUTPase enzyme is essential in Mycobacterium smegmatis.PloS one · 2012Article
- Structural comparisons of host and African swine fever virus dUTPases reveal new clues for inhibitor development.The Journal of biological chemistryArticle
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
We investigated the potential (d)NDP/(d)NTP discrimination mechanisms in nucleotide pyrophosphatases. Here, we report that dUTPase, an essential nucleotide pyrophosphatase, uses a C-terminal P-loop-like sequence in a unique mechanism for substrate discrimination and efficient hydrolysis. Our spectroscopy and transient kinetics results on human dUTPase mutants combined with previous structural studies indicate that (i) H-bond interactions between the γ-phosphate and the P-loop-like motif V promote the catalytically competent conformation of the reaction center at the α-phosphate group; (ii) these interactions accelerate the chemical step of the kinetic cycle and that (iii) hydrolysis occurs very slowly or not at all in the absence of the γ-phosphate--motif V interactions, i.e., in dUDP, dUDP.BeFx, or in the motif V-deleted mutant. The physiological role of dUTPase is to set cellular dUTPdTTP ratios and prevent injurious uracil incorporation into DNA. Based upon comparison with related pyrophosphate generating (d)NTPases, we propose that the unusual use of a P-loop-like motif enables dUTPases to achieve efficient catalysis of dUTP hydrolysis and efficient discrimination against dUDP at the same time. These specifics might have been advantageous on the appearance of uracil-DNA repair. The similarities and differences between dUTPase motif V and the P-loop (or Walker A sequence) commonly featured by ATP- and GTPases offer insight into functional adaptation to various nucleotide hydrolysis tasks.
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