Details for: DPYS

Gene ID: 1807

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: DPYS

Ensembl ID: ENSG00000147647

Description: dihydropyrimidinase

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • midzonal region hepatocyte CL0019028
    CSI 9.65
    rCSI 22.66%
    PRS 94.23
  • epithelial cell of proximal tubule CL0002306
    CSI 8.59
    rCSI 20.99%
    PRS 92.57
  • centrilobular region hepatocyte CL0019029
    CSI 7.47
    rCSI 19.5%
    PRS 93.27
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 7.46
    rCSI 19.45%
    PRS 97.65
  • Kupffer cell CL0000091
    CSI 7.4
    rCSI 16.92%
    PRS 97.13
  • L6b glutamatergic cortical neuron CL4023038
    CSI 7.26
    rCSI 22.69%
    PRS 91.08
  • epithelial cell of proximal tubule segment 3 CL4030011
    CSI 5.44
    rCSI 43.26%
    PRS 92.73
  • hepatocyte CL0000182
    CSI 5.28
    rCSI 9.45%
    PRS 95.07
  • hepatic stellate cell CL0000632
    CSI 4.76
    rCSI 17.84%
    PRS 95.04
  • secretory cell CL0000151
    CSI 4.5
    rCSI 4.7%
    PRS 96.22
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 4.24
    rCSI 15.26%
    PRS 89.01
  • periportal region hepatocyte CL0019026
    CSI 4.19
    rCSI 16.28%
    PRS 93.76
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 4.08
    rCSI 15.43%
    PRS 90.38
  • parietal epithelial cell CL1000452
    CSI 3.67
    rCSI 9.82%
    PRS 94.28
  • intrahepatic cholangiocyte CL0002538
    CSI 3.24
    rCSI 7.78%
    PRS 96.1
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.55
    rCSI 6.46%
    PRS 93.87
  • kidney proximal convoluted tubule epithelial cell CL1000838
    CSI 2.03
    rCSI 21.54%
    PRS 92.72
  • podocyte CL0000653
    CSI 0.78
    rCSI 3.47%
    PRS 96.56
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.34
    rCSI 8.23%
    PRS 87.83
  • direct pathway medium spiny neuron CL4023026
    CSI 0.32
    rCSI 7.69%
    PRS 88.09

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [DPYS](/details-gene/1807) is the protein-coding gene that encodes dihydropyrimidinase, a key metalloenzyme in the pyrimidine degradation pathway. Functionally, it catalyzes the second step in the catabolism of pyrimidines, specifically the ring-opening of dihydrouracil and dihydrothymine. This role places it as a crucial component of nucleotide homeostasis. Expression data from the **Overall** context indicates that [DPYS](/details-gene/1807) is most significantly expressed in metabolically active cells, particularly [midzonal region hepatocyte](/details-cell/CL0019028) in the liver and [epithelial cell of proximal tubule](/details-cell/CL0002306) in the kidney. Clinically, mutations in [DPYS](/details-gene/1807) are associated with dihydropyrimidinase deficiency ([222748](https://omim.org/entry/222748)), an inborn error of pyrimidine metabolism. ## Cellular Roles and Expression Landscape The expression profile of [DPYS](/details-gene/1807) highlights its central role in metabolic tissues. **Overall**, the gene shows the highest significance in the liver and kidney. Specifically, it is a top marker for multiple [hepatocyte](/details-cell/CL0000182) subtypes, including [midzonal region hepatocyte](/details-cell/CL0019028) (CSI: 9.65), [centrilobular region hepatocyte](/details-cell/CL0019029) (CSI: 7.47), and [periportal region hepatocyte](/details-cell/CL0019026) (CSI: 4.19), which is consistent with the liver's function in systemic metabolism and has been confirmed in proteomic studies of human liver ([Link](https://doi.org/10.1016/j.jprot.2013.11.014)). In the kidney, [DPYS](/details-gene/1807) is highly significant in [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 8.59), suggesting a role in processing and reabsorbing filtered metabolites. Other liver-resident cells, such as [Kupffer cell](/details-cell/CL0000091) (CSI: 7.40) and [hepatic stellate cell](/details-cell/CL0000632) (CSI: 4.76), also exhibit high significance scores. Interestingly, notable expression is also observed in specific neuronal populations, such as [L6b glutamatergic cortical neuron](/details-cell/CL4023038) (CSI: 7.26), which may indicate a specialized role for pyrimidine catabolism in the central nervous system. The differential tissue distribution of this enzyme and its related proteins has been previously characterized ([Link](https://doi.org/10.1016/s0378-1119(96)00445-3)). ## Pathways and Molecular Function The function of the [DPYS](/details-gene/1807) gene product is well-defined within nucleotide metabolism. Its primary molecular function is [dihydropyrimidinase activity](/details-cell/GO:0004157), and it requires [zinc ion binding](/details-cell/GO:0008270) for its catalytic function. The enzyme is localized to the [cytosol](/details-cell/GO:0005829). This activity is integral to the Reactome pathway [Pyrimidine catabolism](/details-cell/R-HSA-73621), a part of the broader [Metabolism of nucleotides](/details-cell/R-HSA-15869) super-pathway. Specifically, it participates in several key biological processes, including [uracil catabolic process](/details-cell/GO:0006212) and [thymine catabolic process](/details-cell/GO:0006210). This catabolic function is consistent with its high expression in the liver and kidneys, organs responsible for breaking down metabolic byproducts for excretion. The clinical syndrome of dihydropyrimidinase deficiency arises from the loss of this function, leading to the accumulation of dihydropyrimidines ([Link](https://doi.org/10.1086/302022)). ## Research Directions Based on its function and expression patterns, several research avenues for [DPYS](/details-gene/1807) can be proposed. **Proposed Hypotheses:** 1. The significant expression of [DPYS](/details-gene/1807) in specific neuronal subtypes, such as [L6b glutamatergic cortical neuron](/details-cell/CL4023038), suggests a specialized role in neural metabolism. It is hypothesized that local pyrimidine catabolism by [DPYS](/details-gene/1807) is essential for maintaining nucleotide pools required for neurotransmission or neuronal health, and its dysregulation could contribute to neurological symptoms occasionally observed in patients with dihydropyrimidinase deficiency. 2. Given that [DPYS](/details-gene/1807) is a key enzyme in the catabolism of pyrimidines, its activity level in the liver is hypothesized to be a critical determinant of the pharmacokinetics of pyrimidine-based chemotherapies (e.g., 5-fluorouracil). Genetic or acquired variations in [DPYS](/details-gene/1807) expression or function may explain inter-individual differences in drug toxicity and efficacy. **Experimental Approach:** To test the second hypothesis, one could employ a CRISPR-Cas9-based approach to knock out [DPYS](/details-gene/1807) in a human hepatocyte cell line (e.g., HepG2). Wild-type and knockout cells would be treated with 5-fluorouracil. The rate of drug catabolism would be quantified over time using liquid chromatography-mass spectrometry (LC-MS) to measure the concentrations of 5-FU and its downstream catabolites. A significant reduction in the rate of 5-FU clearance in knockout cells compared to controls would provide direct evidence for the enzyme's role in drug metabolism. **Therapeutic Potential:** The therapeutic relevance of [DPYS](/details-gene/1807) is twofold. For the inherited disorder of dihydropyrimidinase deficiency ([222748](https://omim.org/entry/222748)), the goal would be functional restoration, potentially through enzyme replacement or gene therapy. In the context of oncology, [DPYS](/details-gene/1807) represents a potential target for **inhibition**. By inhibiting its activity, the catabolism of pyrimidine-based anticancer drugs could be slowed, thereby increasing their bioavailability and therapeutic index. However, systemic inhibition would require careful consideration of its impact on normal pyrimidine homeostasis, particularly given its high expression in vital organs like the liver and kidneys.

Genular Protein ID: 1682929951

Symbol: DPYS_HUMAN

Name: Dihydropyrimidinase

UniProtKB Accession Codes:

Q14117

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 12 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 3 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 13 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MEROPS 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8973361

Title: A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution.

PubMed ID: 8973361

DOI: 10.1016/s0378-1119(96)00445-3

PubMed ID: 9718352

Title: Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene.

PubMed ID: 9718352

DOI: 10.1086/302022

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

Sequence Information:

  • Length: 519
  • Mass: 56630
  • Checksum: 882E33D7C49D6ECC
  • Sequence:
    • MAAPSRLLIR GGRVVNDDFS EVADVLVEDG VVRALGHDLL PPGGAPAGLR VLDAAGKLVL 
PGGIDTHTHM QFPFMGSRSI DDFHQGTKAA LSGGTTMIID FAIPQKGGSL IEAFETWRSW 
ADPKVCCDYS LHVAVTWWSD QVKEEMKILV QDKGVNSFKM FMAYKDLYMV TDLELYEAFS 
RCKEIGAIAQ VHAENGDLIA EGAKKMLALG ITGPEGHELC RPEAVEAEAT LRAITIASAV 
NCPLYIVHVM SKSAAKVIAD ARRDGKVVYG EPIAASLGTD GTHYWNKEWH HAAHHVMGPP 
LRPDPSTPDF LMNLLANDDL TTTGTDNCTF NTCQKALGKD DFTKIPNGVN GVEDRMSVIW 
EKGVHSGKMD ENRFVAVTST NAAKIFNLYP RKGRIAVGSD ADIVIWDPKG TRTISAKTHH 
QAVNFNIFEG MVCHGVPLVT ISRGKVVYEA GVFSVTAGDG KFIPRKPFAE YIYKRIKQRD 
RTCTPTPVER APYKGEVATL KSRVTKEDAT AGTRKQAHP