ArticleNature communications2023
Mechanism of substrate hydrolysis by the human nucleotide pool sanitiser DNPH1.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
What it found
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.
- Identification of therapeutic targets for insomnia through genetic and plasma proteomic approaches.Medicine · 2025Pooled it
- Structural Basis for Nucleobase Activation by the Adenine DNA Glycosylase MutY.Chembiochem : a European journal of chemical biology · 2026Article
- Structural Basis for Nucleobase Activation by the Adenine DNA Glycosylase MutY.bioRxiv : the preprint server for biology · 2026Article
- The energy landscape of N-ribosidic bond cleavage catalysed by 2'-deoxynucleoside 5'-phosphate N-hydrolase 1.The Biochemical journal · 2025Article
- Identification of breast cancer susceptibility genes via trans-ethnic Mendelian randomization and colocalization analyses.Medicine · 2025Article
- Hsa_circ_0038737 promotes PARPi resistance in castration-resistant prostate cancer via IGF2BP3-mediated DNPH1 mRNA stabilization.Molecular cancer · 2025Article
- Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy.Cancer gene therapy · 2024Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the clinic to treat BRCA-deficient breast, ovarian and prostate cancers. As their efficacy is potentiated by loss of the nucleotide salvage factor DNPH1 there is considerable interest in the development of highly specific small molecule DNPH1 inhibitors. Here, we present X-ray crystal structures of dimeric DNPH1 bound to its substrate hydroxymethyl deoxyuridine monophosphate (hmdUMP). Direct interaction with the hydroxymethyl group is important for substrate positioning, while conserved residues surrounding the base facilitate target discrimination. Glycosidic bond cleavage is driven by a conserved catalytic triad and proceeds via a two-step mechanism involving formation and subsequent disruption of a covalent glycosyl-enzyme intermediate. Mutation of a previously uncharacterised yet conserved glutamate traps the intermediate in the active site, demonstrating its role in the hydrolytic step. These observations define the enzyme's catalytic site and mechanism of hydrolysis, and provide important insights for inhibitor discovery.
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