Details for: PGA4

Gene ID: 643847

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: PGA4

Ensembl ID: ENSG00000229183

Description: pepsinogen A4

Cell Significance Landscape

Associated with

Significant Cells

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

  • mucous neck cell CL0000651
    CSI 14.79
    rCSI 21.32%
    PRS 99.97
  • peptic cell CL0000155
    CSI 2.48
    rCSI 24.38%
    PRS 99.89
  • parietal cell CL0000162
    CSI 1.99
    rCSI 17.13%
    PRS 99.88

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

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • 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 [PGA4](/details-gene/643847), or Pepsinogen A4, is a protein-coding gene located on chromosome 11. It encodes an aspartic protease that functions as a zymogen, or inactive precursor, of the digestive enzyme pepsin A. As a key component of the gastric juices, its primary role is in the initial stages of protein digestion within the stomach. Consistent with this function, its expression is highly specific to secretory cells of the gastric mucosa. Genetic and protein characterization studies have elucidated its structure and activation mechanism ([Link](https://doi.org/10.1016/s0021-9258(18)32572-9), [Link](https://doi.org/10.1016/0014-5793(88)81033-0)). This gene is part of a larger family of pepsinogen A genes and is associated with clinical phenotypes cataloged under OMIM entry [169720](https://omim.org/entry/169720). ## Cellular Roles and Expression Landscape The expression profile of [PGA4](/details-gene/643847) is narrowly restricted to specialized cell types within the stomach lining, underscoring its dedicated role in digestion. **Overall**, the gene shows the highest significance and specificity in the [mucous neck cell](/details-cell/CL0000651) (CSI: 14.79), a cell type found in the gastric pits responsible for secreting mucus. This exceptionally high score suggests [PGA4](/details-gene/643847) is a defining molecular marker for this cellular lineage. Significant expression is also observed in other key gastric secretory cells, including the [peptic cell](/details-cell/CL0000155) (CSI: 2.48), which is the primary producer of pepsinogen, and the [parietal cell](/details-cell/CL0000162) (CSI: 1.99), responsible for acid secretion. This co-localization within the functional unit of the gastric gland highlights its integral role in the coordinated process of gastric digestion. The data strongly indicate that [PGA4](/details-gene/643847) expression is a hallmark of the gastric secretory epithelium. ## Pathways and Molecular Function The molecular functions attributed to [PGA4](/details-gene/643847) align precisely with its physiological role as a digestive enzyme precursor. Gene Ontology (GO) annotations confirm its involvement in **Biological Processes** such as 'Digestion' ([GO:0007586](https://www.ebi.ac.uk/QuickGO/term/GO:0007586)) and 'Proteolysis' ([GO:0006508](https://www.ebi.ac.uk/QuickGO/term/GO:0006508)). Its **Molecular Function** is specified as 'Aspartic-type endopeptidase activity' ([GO:0004190](https://www.ebi.ac.uk/QuickGO/term/GO:0004190)), characteristic of pepsins. The annotation for **Cellular Component** lists 'Extracellular exosome' ([GO:0070062](https://www.ebi.ac.uk/QuickGO/term/GO:0070062)), which is consistent with its synthesis within gastric cells and subsequent secretion into the gastric lumen for activation. This is further supported by the Reactome pathway annotation for 'Metabolism of proteins' ([R-HSA-392499](https://reactome.org/content/detail/R-HSA-392499)), where pepsin initiates the breakdown of dietary proteins. The involvement in 'Surfactant metabolism' ([R-HSA-5683826](https://reactome.org/content/detail/R-HSA-5683826)) may suggest broader, less characterized roles or interactions within the gastric mucosal environment. ## Research Directions Given the highly specific expression of [PGA4](/details-gene/643847) in gastric mucosal cells, future research should focus on its potential role as a biomarker for gastric health and disease, as well as the functional consequences of its dysregulation. **Testable Hypotheses:** 1. **Hypothesis 1:** The expression level of [PGA4](/details-gene/643847) within [mucous neck cell](/details-cell/CL0000651)s is significantly altered during the progression of chronic gastritis to gastric intestinal metaplasia, a pre-cancerous lesion. This alteration could serve as a sensitive and specific early biomarker for disease progression. 2. **Hypothesis 2:** Genetic polymorphisms or mutations within the [PGA4](/details-gene/643847) gene, particularly in regions governing its activation peptide, may lead to aberrant pepsin activity, contributing to an individual's susceptibility to peptic ulcer disease or gastroesophageal reflux disease (GERD). **Proposed Experiment:** To test the first hypothesis regarding [PGA4](/details-gene/643847) as a biomarker, a study utilizing spatial transcriptomics on a cohort of human gastric biopsy samples would be highly informative. This approach would allow for the precise quantification of [PGA4](/details-gene/643847) mRNA levels specifically within the [mucous neck cell](/details-cell/CL0000651) population across different histological stages, from normal mucosa to chronic gastritis, intestinal metaplasia, and gastric adenocarcinoma. Correlating gene expression levels with pathological scores and patient outcomes could validate its utility as a prognostic or diagnostic marker. **Therapeutic Potential:** Direct therapeutic targeting of [PGA4](/details-gene/643847) is unlikely, as it is a crucial component of normal digestion. Its encoded protein, pepsin, is already the target of broad-acting acid-suppressive therapies that create a less favorable environment for its activity. However, its high tissue specificity makes it an excellent candidate for development as a diagnostic or prognostic biomarker. Circulating levels of pepsinogen are already used to assess gastric mucosal health. Future advancements could involve developing more sensitive assays specific to the PGA4 isozyme or using its promoter to drive the expression of therapeutic genes specifically in gastric secretory cells for targeted gene therapy applications in gastric diseases.

Genular Protein ID: 3791448760

Symbol: PEPA4_HUMAN

Name: Pepsin A-4

UniProtKB Accession Codes:

P0DJD7 A8K749 B7ZW75 P00790 Q7M4R0 Q8N1E3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 2 EMBL 15 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 5 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 2 MIM 2 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 4 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 1 RefSeq 2 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 6300126

Title: Primary structure of human pepsinogen gene.

PubMed ID: 6300126

DOI: 10.1016/s0021-9258(18)32572-9

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

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: 2415509

Title: Isolation of human, swine, and rat prepepsinogens and calf preprochymosin, and determination of the primary structures of their NH2-terminal signal sequences.

PubMed ID: 2415509

DOI: 10.1093/oxfordjournals.jbchem.a135303

PubMed ID: 2515193

Title: A comparative study on the NH2-terminal amino acid sequences and some other properties of six isozymic forms of human pepsinogens and pepsins.

PubMed ID: 2515193

DOI: 10.1093/oxfordjournals.jbchem.a122952

PubMed ID: 3197840

Title: Activation of human pepsinogens.

PubMed ID: 3197840

DOI: 10.1016/0014-5793(88)81033-0

PubMed ID: 4909888

Title: Carboxyl-terminal sequence of human gastricsin and pepsin.

PubMed ID: 4909888

DOI: 10.1016/s0021-9258(18)63137-0

PubMed ID: 2714789

Title: Nucleotide sequence comparison of five human pepsinogen A (PGA) genes: evolution of the PGA multigene family.

PubMed ID: 2714789

DOI: 10.1016/0888-7543(89)90325-x

PubMed ID: 7663352

Title: Crystal structure of human pepsin and its complex with pepstatin.

PubMed ID: 7663352

DOI: 10.1002/pro.5560040516

Sequence Information:

  • Length: 388
  • Mass: 41977
  • Checksum: C9CB89BA08F4D78B
  • Sequence:
    • MKWLLLLGLV ALSECIMYKV PLIRKKSLRR TLSERGLLKD FLKKHNLNPA RKYFPQWEAP 
TLVDEQPLEN YLDMEYFGTI GIGTPAQDFT VVFDTGSSNL WVPSVYCSSL ACTNHNRFNP 
EDSSTYQSTS ETVSITYGTG SMTGILGYDT VQVGGISDTN QIFGLSETEP GSFLYYAPFD 
GILGLAYPSI SSSGATPVFD NIWNQGLVSQ DLFSVYLSAD DQSGSVVIFG GIDSSYYTGS 
LNWVPVTVEG YWQITVDSIT MNGEAIACAE GCQAIVDTGT SLLTGPTSPI ANIQSDIGAS 
ENSDGDMVVS CSAISSLPDI VFTINGVQYP VPPSAYILQS EGSCISGFQG MNLPTESGEL 
WILGDVFIRQ YFTVFDRANN QVGLAPVA

Genular Protein ID: 1538222349

Symbol: B7Z719_HUMAN

Name: N/A

UniProtKB Accession Codes:

B7Z719

Database IDs:

ARBA 5 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 3 InterPro 5 KEGG 1 MEROPS 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PROSITE 3 PeptideAtlas 1 Pfam 2 RefSeq 1 RuleBase 1 SAM 1 SMR 1 SUPFAM 1

Sequence Information:

  • Length: 212
  • Mass: 23425
  • Checksum: 83E18EC8775ADACF
  • Sequence:
    • MKWLLLLGLV ALSECIMYKV PLIRKKSLRR TLSERGLLKD FLKKHNLNPA RKYFPQWEAP 
TLVDEQPLEN YLDMEYFGTI GIGTPAQDFT VVFDTGSSNL WVPSVYCSSL ACPIANIQSD 
IGASENSDGD MVVSCSAISS LPDIVFTING VQYPVPPSAY ILQSEGSCIS GFQGMNLPTE 
SGELWILGDV FIRQYFTVFD RANNQVGLAP VA