Details for: ENPEP

Gene ID: 2028

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: ENPEP

Ensembl ID: ENSG00000138792

Description: glutamyl aminopeptidase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • vascular leptomeningeal cell CL4023051
    CSI 13.32
    rCSI 23.35%
    PRS 88.27
  • colonocyte CL1000347
    CSI 11.24
    rCSI 16.12%
    PRS 89.62
  • extravillous trophoblast CL0008036
    CSI 7.93
    rCSI 9.81%
    PRS 89.99
  • epithelial cell of proximal tubule CL0002306
    CSI 7.49
    rCSI 18.3%
    PRS 85.55
  • periportal region hepatocyte CL0019026
    CSI 7.45
    rCSI 28.98%
    PRS 88.5
  • podocyte CL0000653
    CSI 6.39
    rCSI 28.38%
    PRS 91.8
  • fibroblast of lung CL0002553
    CSI 5.43
    rCSI 5.05%
    PRS 92.85
  • ependymal cell CL0000065
    CSI 5.04
    rCSI 10.22%
    PRS 74.92
  • alveolar type 1 fibroblast cell CL4028004
    CSI 4.7
    rCSI 5.15%
    PRS 93.06
  • hepatic stellate cell CL0000632
    CSI 4.67
    rCSI 17.49%
    PRS 87.58
  • enterocyte CL0000584
    CSI 4.59
    rCSI 7.4%
    PRS 88.78
  • myofibroblast cell CL0000186
    CSI 4.39
    rCSI 6.07%
    PRS 88.51
  • goblet cell CL0000160
    CSI 3.9
    rCSI 3.68%
    PRS 89.52
  • vascular associated smooth muscle cell CL0000359
    CSI 3.52
    rCSI 11.41%
    PRS 89.85
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 3.47
    rCSI 9.04%
    PRS 93.06
  • sncg GABAergic cortical interneuron CL4023015
    CSI 3.38
    rCSI 5.44%
    PRS 80.55
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 3.16
    rCSI 4.48%
    PRS 89.61
  • basal cell of epidermis CL0002187
    CSI 3.05
    rCSI 5.41%
    PRS 63.97
  • pericyte CL0000669
    CSI 2.97
    rCSI 7.92%
    PRS 69.56
  • perivascular cell CL4033054
    CSI 2.68
    rCSI 3.66%
    PRS 94.24
  • parietal epithelial cell CL1000452
    CSI 2.65
    rCSI 7.09%
    PRS 86.74
  • type L enteroendocrine cell CL0002279
    CSI 2.62
    rCSI 4.92%
    PRS 93.13
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.37
    rCSI 6.02%
    PRS 85.99
  • renal interstitial pericyte CL1001318
    CSI 2.33
    rCSI 6.43%
    PRS 89.19
  • centrilobular region hepatocyte CL0019029
    CSI 1.97
    rCSI 5.14%
    PRS 87.65
  • alveolar adventitial fibroblast CL4028006
    CSI 1.91
    rCSI 3.01%
    PRS 92.37
  • enterocyte of epithelium of small intestine CL1000334
    CSI 1.8
    rCSI 27.92%
    PRS 93.75
  • BEST4+ enteroycte CL4030026
    CSI 1.68
    rCSI 2.09%
    PRS 91.2
  • small intestine goblet cell CL1000495
    CSI 1.64
    rCSI 3.59%
    PRS 93.42
  • placental villous trophoblast CL2000060
    CSI 1.61
    rCSI 2.49%
    PRS 89.81
  • contractile cell CL0000183
    CSI 1.47
    rCSI 4.35%
    PRS 90.94
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.47
    rCSI 3.8%
    PRS 89.15
  • enteroendocrine cell of small intestine CL0009006
    CSI 1.44
    rCSI 3.18%
    PRS 93.91
  • keratocyte CL0002363
    CSI 1.4
    rCSI 3.37%
    PRS 92.51
  • microcirculation associated smooth muscle cell CL0008035
    CSI 1.35
    rCSI 3.91%
    PRS 90.82
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.32
    rCSI 3.56%
    PRS 93.39
  • fibroblast of breast CL4006000
    CSI 1.13
    rCSI 4.74%
    PRS 93.1
  • paneth cell of epithelium of small intestine CL1000343
    CSI 1
    rCSI 2.79%
    PRS 94.11
  • blood vessel smooth muscle cell CL0019018
    CSI 0.96
    rCSI 7.84%
    PRS 89.3
  • type EC enteroendocrine cell CL0000577
    CSI 0.76
    rCSI 2.7%
    PRS 92.7
  • transit amplifying cell of small intestine CL0009012
    CSI 0.66
    rCSI 2.88%
    PRS 94.42
  • pancreatic stellate cell CL0002410
    CSI 0.56
    rCSI 3.24%
    PRS 92.9

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.

Comma-separated if multiple.
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)

Loading network (please wait)...

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 [ENPEP](/details-gene/2028), or glutamyl aminopeptidase (also known as aminopeptidase A), is a protein-coding gene located on chromosome 4q25. It encodes a zinc-dependent metalloaminopeptidase that plays a crucial role in the renin-angiotensin system by converting angiotensin II to angiotensin III. This function positions [ENPEP](/details-gene/2028) as a key regulator of blood pressure and fluid balance. **Overall**, expression data reveals its high significance in specialized cell types across multiple organ systems, including the vasculature, kidney, intestine, and placenta. Its primary roles are linked to peptide catabolism, particularly in the context of peptide hormone metabolism ([R-HSA-2980736](https://reactome.org/content/detail/R-HSA-2980736)), cell migration ([GO:0016477](https://www.ebi.ac.uk/QuickGO/term/GO:0016477)), and angiogenesis ([GO:0001525](https://www.ebi.ac.uk/QuickGO/term/GO:0001525)). ## Cellular Roles and Expression Landscape The expression profile of [ENPEP](/details-gene/2028) highlights its specialized function in tissues responsible for transport, filtration, and barrier integrity. The gene shows the highest significance in [vascular leptomeningeal cells](/details-cell/CL4023051) (CSI: 13.32), suggesting a role in regulating the cerebrovascular environment and blood-brain barrier. Its prominence in intestinal epithelial cells, such as [colonocytes](/details-cell/CL1000347) (CSI: 11.24) and [enterocytes](/details-cell/CL0000584) (CSI: 4.59), is consistent with its localization to the brush border ([GO:0005903](https://www.ebi.ac.uk/QuickGO/term/GO:0005903)) and apical plasma membrane ([GO:0016324](https://www.ebi.ac.uk/QuickGO/term/GO:0016324)), where it likely participates in the final digestion of peptides. A critical role for [ENPEP](/details-gene/2028) in renal and placental physiology is strongly supported by the data. It is a significant marker in key kidney cells, including [epithelial cells of the proximal tubule](/details-cell/CL0002306) (CSI: 7.49) and [podocytes](/details-cell/CL0000653) (CSI: 6.39), which aligns with its established function in blood pressure regulation via angiotensin metabolism. Furthermore, its high significance in [extravillous trophoblasts](/details-cell/CL0008036) (CSI: 7.93) points to a role in placental development and uterine invasion, a process requiring angiogenesis and cell migration, as noted in one study [Link](https://doi.org/10.1053/plac.1999.0456). The gene is also highly expressed in various mesenchymal and stromal cells, including [fibroblasts of the lung](/details-cell/CL0002553) (CSI: 5.43) and [hepatic stellate cells](/details-cell/CL0000632) (CSI: 4.67), suggesting a broader involvement in tissue structure and remodeling. ## Pathways and Molecular Function Functionally, [ENPEP](/details-gene/2028) is a metalloaminopeptidase ([GO:0070006](https://www.ebi.ac.uk/QuickGO/term/GO:0070006)) that requires zinc ion binding ([GO:0008270](https://www.ebi.ac.uk/QuickGO/term/GO:0008270)) for its catalytic activity. Its most well-characterized function is its participation in the renin-angiotensin system, specifically the [Metabolism of angiotensinogen to angiotensins](/details-reactome/R-HSA-2022377) ([R-HSA-2022377](https://reactome.org/content/detail/R-HSA-2022377)). By cleaving the N-terminal glutamate residue from angiotensin II to form angiotensin III, it directly contributes to the [Regulation of systemic arterial blood pressure by renin-angiotensin](/details-go/GO:0003081) ([GO:0003081](https://www.ebi.ac.uk/QuickGO/term/GO:0003081)). The cloning and initial characterization of this enzyme were detailed in several key publications [Link](https://doi.org/10.1073/pnas.90.15.7069), [Link](https://doi.org/10.1006/geno.1993.1386). Beyond blood pressure control, its peptidase activity is implicated in broader biological processes. The gene's involvement in [Angiogenesis](/details-go/GO:0001525) ([GO:0001525](https://www.ebi.ac.uk/QuickGO/term/GO:0001525)) and [Cell migration](/details-go/GO:0016477) ([GO:0016477](https://www.ebi.ac.uk/QuickGO/term/GO:0016477)) suggests it may process peptides that act as signaling molecules to guide these cellular behaviors, a function particularly relevant to its high expression in [extravillous trophoblasts](/details-cell/CL0008036) during placental development. As a membrane-bound enzyme, it is primarily located on the external side of the plasma membrane ([GO:0009897](https://www.ebi.ac.uk/QuickGO/term/GO:0009897)), allowing it to act on substrates in the extracellular space. ## Research Directions The specific, high-level expression of [ENPEP](/details-gene/2028) in distinct cell types offers avenues for targeted research into its physiological and pathological roles. ### Proposed Hypotheses 1. **Cell-specific renal regulation:** The high significance of [ENPEP](/details-gene/2028) in both [podocytes](/details-cell/CL0000653) and [epithelial cells of the proximal tubule](/details-cell/CL0002306) suggests that its activity in these specific renal compartments may have distinct and non-redundant effects on blood pressure and glomerular filtration. We hypothesize that podocyte-expressed [ENPEP](/details-gene/2028) primarily regulates local glomerular hemodynamics, while tubular [ENPEP](/details-gene/2028) is more involved in systemic sodium and water reabsorption. 2. **Role in placental pathology:** Given its high expression in invasive [extravillous trophoblasts](/details-cell/CL0008036) and its association with angiogenesis, we hypothesize that insufficient [ENPEP](/details-gene/2028) activity impairs trophoblast migration and uterine spiral artery remodeling, leading to placental ischemia and contributing to the pathogenesis of pre-eclampsia. ### Experimental Approach To test the first hypothesis regarding the cell-specific roles of [ENPEP](/details-gene/2028) in the kidney, a series of experiments using conditional knockout mice could be conducted. `Enpep flox/flox` mice would be crossed with two different Cre driver lines: one specific to podocytes (e.g., *Nphs2-Cre*) and another specific to the proximal tubule (e.g., *Sglt2-Cre*). The resulting conditional knockout mice, along with control littermates, would be subjected to hypertensive stimuli such as an angiotensin II infusion or a high-salt diet. The differential impact of podocyte-specific vs. tubule-specific knockout on systemic blood pressure (measured via telemetry), albuminuria (a marker of glomerular damage), and kidney histology would elucidate the precise contribution of [ENPEP](/details-gene/2028) in each cell type to renal-dependent hypertension. ### Therapeutic Potential [ENPEP](/details-gene/2028) represents a highly promising therapeutic target, particularly for cardiovascular disease. As a cell-surface enzyme with a well-defined active site, it is amenable to small-molecule inhibition. Structural studies have already provided a basis for rational drug design [Link](https://doi.org/10.1074/jbc.m113.494955). **Inhibition** of [ENPEP](/details-gene/2028) could provide a novel therapeutic strategy for hypertension, complementing existing therapies like ACE inhibitors by targeting a different node in the renin-angiotensin cascade. The development of inhibitors that are selectively delivered to or activated within the kidney could offer a more targeted approach with fewer systemic side effects than current treatments.

Genular Protein ID: 2068981603

Symbol: AMPE_HUMAN

Name: Glutamyl aminopeptidase

UniProtKB Accession Codes:

Q07075 Q504U2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 4 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EC 1 EMBL 5 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 24 Gene3D 4 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 7 PDBsum 7 PIR 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8346219

Title: Molecular cloning of the human kidney differentiation antigen gp160: human aminopeptidase A.

PubMed ID: 8346219

DOI: 10.1073/pnas.90.15.7069

PubMed ID: 8244382

Title: cDNA cloning and expression of human glutamyl aminopeptidase (aminopeptidase A).

PubMed ID: 8244382

DOI: 10.1006/geno.1993.1386

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

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: 10692253

Title: Expression of aminopeptidase A in human gestational choriocarcinoma cell lines and tissues.

PubMed ID: 10692253

DOI: 10.1053/plac.1999.0456

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 23888046

Title: Structural insights into central hypertension regulation by human aminopeptidase A.

PubMed ID: 23888046

DOI: 10.1074/jbc.m113.494955

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 957
  • Mass: 109244
  • Checksum: AB6407432A45A7C6
  • Sequence:
    • MNFAEREGSK RYCIQTKHVA ILCAVVVGVG LIVGLAVGLT RSCDSSGDGG PGTAPAPSHL 
PSSTASPSGP PAQDQDICPA SEDESGQWKN FRLPDFVNPV HYDLHVKPLL EEDTYTGTVS 
ISINLSAPTR YLWLHLRETR ITRLPELKRP SGDQVQVRRC FEYKKQEYVV VEAEEELTPS 
SGDGLYLLTM EFAGWLNGSL VGFYRTTYTE NGQVKSIVAT DHEPTDARKS FPCFDEPNKK 
ATYTISITHP KEYGALSNMP VAKEESVDDK WTRTTFEKSV PMSTYLVCFA VHQFDSVKRI 
SNSGKPLTIY VQPEQKHTAE YAANITKSVF DYFEEYFAMN YSLPKLDKIA IPDFGTGAME 
NWGLITYRET NLLYDPKESA SSNQQRVATV VAHELVHQWF GNIVTMDWWE DLWLNEGFAS 
FFEFLGVNHA ETDWQMRDQM LLEDVLPVQE DDSLMSSHPI IVTVTTPDEI TSVFDGISYS 
KGSSILRMLE DWIKPENFQK GCQMYLEKYQ FKNAKTSDFW AALEEASRLP VKEVMDTWTR 
QMGYPVLNVN GVKNITQKRF LLDPRANPSQ PPSDLGYTWN IPVKWTEDNI TSSVLFNRSE 
KEGITLNSSN PSGNAFLKIN PDHIGFYRVN YEVATWDSIA TALSLNHKTF SSADRASLID 
DAFALARAQL LDYKVALNLT KYLKREENFL PWQRVISAVT YIISMFEDDK ELYPMIEEYF 
QGQVKPIADS LGWNDAGDHV TKLLRSSVLG FACKMGDREA LNNASSLFEQ WLNGTVSLPV 
NLRLLVYRYG MQNSGNEISW NYTLEQYQKT SLAQEKEKLL YGLASVKNVT LLSRYLDLLK 
DTNLIKTQDV FTVIRYISYN SYGKNMAWNW IQLNWDYLVN RYTLNNRNLG RIVTIAEPFN 
TELQLWQMES FFAKYPQAGA GEKPREQVLE TVKNNIEWLK QHRNTIREWF FNLLESG