DNPH1

Last update 08 May 2025

Basic Info

Synonyms

2'-deoxynucleoside 5'-phosphate N-hydrolase 1, c-Myc-responsive protein RCL, C6orf108

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Introduction

Part of a nucleotide salvage pathway that eliminates epigenetically modified 5-hydroxymethyl-dCMP (hmdCMP) in a two-step process entailing deamination to cytotoxic 5-hydroxymethyl-dUMP (hmdUMP), followed by its hydrolysis into 5-hydroxymethyluracil (hmU) and 2-deoxy-D-ribose 5-phosphate (deoxyribosephosphate) (PubMed:33833118). Catalyzes the second step in that pathway, the hydrolysis of the N-glycosidic bond in hmdUMP, degrading this cytotoxic nucleotide to avoid its genomic integration (PubMed:33833118).

100 Clinical Results associated with DNPH1

100 Translational Medicine associated with DNPH1

0 Patents (Medical) associated with DNPH1

176

Literatures (Medical) associated with DNPH1

01 Jun 2025·Journal of Pharmaceutical and Biomedical Analysis

Identification of potential drug targets for four site-specific cancers by integrating human plasma proteome with genome

Article

Author: Sun, Ziyi ; Tian, Shaodan ; Yun, Zhangjun ; Li, Xiao ; Hou, Li ; Yan, Xiang ; Yang, Qianru ; Liu, Zhu

Drug targets supported by genetic evidence with a several-fold higher probability of success in clinical trials. We performed a comprehensive proteome-wide Mendelian randomization (MR) analysis to identify causal proteins and potential therapeutic targets for four site-specific cancers. A total of 13,248 protein quantitative trait loci for 4853 plasma proteins were utilized for proteome-wide MR analysis. Identification of cancer causal proteins in the discovery cohort and further validation in the replication cohort. Colocalization, summary-data-based MR (SMR) analysis, and transcriptome‑wide association studies (TWAS) were performed to check the accuracy of the candidate proteins. Two-step MR analysis was used to explore the effects of plasma protein-mediated 248 modifiable factors on cancer. Phenome-wide MR (Phe-MR) analysis, druggability evaluation, and single-cell type expression analysis further assessed the potential of causal proteins. Combining the results of the meta-analysis of MR estimates from the two cohorts, 21, 2, 24 and 1 causal proteins were identified in breast, lung, prostate and stomach cancers, respectively. Evidence from colocalization, SMR analysis, and TWAS highlighted CD36, DNPH1, and PLXND1 as the most promising drug targets for breast cancer, and ZNF175 for prostate cancer. 1 new potential biomarker (PLXND1) for breast cancer, 2 new promising targets (RELL1, DEFB119) for lung cancer, and 8 new circulating biomarkers (ARFIP2, CCN6, CTRB2, HTR7, MRPL33, TNFRSF6B, VAMP5, ZNF175) for prostate cancer were firstly reported. Some plasma proteins may mediate the association of these cancers with other systemic diseases. Additionally, genetically predicted higher BMI and overweight may reduce breast cancer risk by altering CASP8, ADM, PLXND1, TNFRSF9, ULK3 and VSIG4 protein levels. Causal proteins of breast and prostate cancer were expressed predominantly on macrophages in cancerous tissues. This study genetically identified several cancer causal proteins which provided new perspectives for the understanding of the etiology and development of novel targeted drugs for cancer.

28 Feb 2025·Glycobiology

RCL glycosylation of serum corticosteroid-binding globulin: implications in cortisol delivery and septic shock

Article

Author: Meyer, Emily J ; Lee, Jessica H ; Torpy, David J ; Thaysen-Andersen, Morten ; Sumer-Bayraktar, Zeynep ; Chernykh, Anastasia

AbstractCorticosteroid-binding globulin (CBG) is a serum glycoprotein that binds and delivers anti-inflammatory cortisol to inflammatory sites through neutrophil elastase-mediated proteolysis of an exposed reactive centre loop (RCL) on CBG. Timely and tissue-specific delivery of cortisol is critical to alleviate inflammation including in life-threatening septic shock conditions. Herein, we firstly summarise our recently published report of functional RCL O- and N-glycosylation events of serum CBG (Chernykh, J Biol Chem, 2023). A key finding of that published work was the LC–MS/MS-based discovery of RCL O-glycans at Thr342 and Thr345 of serum CBG and their inhibitory roles in neutrophil elastase-mediated RCL proteolysis. While these observations are of significance as they implicate RCL O-glycosylation as a potential regulator of cortisol delivery, the link to septic shock remains unexplored. To this end, we used a similar LC–MS/MS approach to profile the RCL O-glycosylation of CBG purified from serum of twelve septic shock patients. Serum CBG from all patients exhibited RCL O-glycosylation comprising (di)sialyl T (NeuAc1-2Gal1GalNAc1) core 1-type O-glycan structures decorating exclusively the Thr342 site. Importantly, relative to less severe cases, individuals presenting with the most severe illness displayed elevated RCL O-glycosylation upon ICU admission, suggesting a previously unknown link to septic shock severity. Overall, we have elucidated the coordinated RCL N- and O-glycosylation events of serum CBG, which improve our understanding of molecular mechanisms governing the timely and tissue-specific delivery of cortisol to inflammatory sites. This work provides clues to molecular aberrations and disease mechanisms underpinning septic shock.

13 Feb 2025·Journal of Medicinal Chemistry

Transition State Analogs of Human DNPH1 Reveal Two Electrophile Migration Mechanisms

Article

Author: Eskandari, Roozbeh ; Ghosh, Agnidipta ; Suthagar, Kajitha ; Ledingham, Edward T. ; Schramm, Vern L. ; Wagner, Andrew G. ; Almo, Steven C. ; Lamiable-Oulaidi, Farah ; Tyler, Peter C. ; Lang, Thomas B. D. ; Brooks, Donovan

DNPH1 is responsible for eliminating the epigenetically modified nucleotide, 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate (hmdUMP), preventing formation of hmdUTP, a mutation-inducing nucleotide. Loss of DNPH1 activity sensitizes PARP inhibition-resistant BRCA-deficient cancers by causing incorporation of hmdUTP into DNA. Hydrolysis of hmdUMP by DNPH1 proceeds through a covalent intermediate between Glu104 and 2-deoxyribose 5-phosphate, followed by hydrolysis, a reaction cycle with two transition states. We describe synthesis and characterization of transition state mimics for both transition states of DNPH1. Both transition states prefer inhibitors with cationic charge at the anomeric center and provide a foundation for inhibitor design. Ground-state complexes show reaction coordinate nucleophiles poised 3.3-3.7 Å from the anomeric carbon while transition state analogs tighten the reaction coordinate to place the nucleophiles 2.7-2.8 Å from the anomeric carbon. Crystal structures of DNPH1 with transition state analogs reveal transition states where the electrophilic ribocation migrates between the leaving groups and attacking nucleophiles.

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DNPH1

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