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ENPEP

Official Full Name
glutamyl aminopeptidase
Organism
Homo sapiens
GeneID
2028
Background
The ENPEP gene encodes glutamyl aminopeptidase, a type II integral membrane protein with an extracellular zinc-binding domain. This protein can upregulate blood pressure by cleaving the N-terminal aspartate from angiotensin II, and can regulate blood vessel formation and enhance tumorigenesis in some tissues. Along with ANPEP and DPP4, ENPEP was found to be a candidate co-receptor for the coronavirus SARS-CoV-2, which causes COVID-19. [provided by RefSeq, Apr 2020]
Synonyms
APA; CD249; gp160;
Bio Chemical Class
Peptidase
Protein Sequence
MNFAEREGSKRYCIQTKHVAILCAVVVGVGLIVGLAVGLTRSCDSSGDGGPGTAPAPSHLPSSTASPSGPPAQDQDICPASEDESGQWKNFRLPDFVNPVHYDLHVKPLLEEDTYTGTVSISINLSAPTRYLWLHLRETRITRLPELKRPSGDQVQVRRCFEYKKQEYVVVEAEEELTPSSGDGLYLLTMEFAGWLNGSLVGFYRTTYTENGQVKSIVATDHEPTDARKSFPCFDEPNKKATYTISITHPKEYGALSNMPVAKEESVDDKWTRTTFEKSVPMSTYLVCFAVHQFDSVKRISNSGKPLTIYVQPEQKHTAEYAANITKSVFDYFEEYFAMNYSLPKLDKIAIPDFGTGAMENWGLITYRETNLLYDPKESASSNQQRVATVVAHELVHQWFGNIVTMDWWEDLWLNEGFASFFEFLGVNHAETDWQMRDQMLLEDVLPVQEDDSLMSSHPIIVTVTTPDEITSVFDGISYSKGSSILRMLEDWIKPENFQKGCQMYLEKYQFKNAKTSDFWAALEEASRLPVKEVMDTWTRQMGYPVLNVNGVKNITQKRFLLDPRANPSQPPSDLGYTWNIPVKWTEDNITSSVLFNRSEKEGITLNSSNPSGNAFLKINPDHIGFYRVNYEVATWDSIATALSLNHKTFSSADRASLIDDAFALARAQLLDYKVALNLTKYLKREENFLPWQRVISAVTYIISMFEDDKELYPMIEEYFQGQVKPIADSLGWNDAGDHVTKLLRSSVLGFACKMGDREALNNASSLFEQWLNGTVSLPVNLRLLVYRYGMQNSGNEISWNYTLEQYQKTSLAQEKEKLLYGLASVKNVTLLSRYLDLLKDTNLIKTQDVFTVIRYISYNSYGKNMAWNWIQLNWDYLVNRYTLNNRNLGRIVTIAEPFNTELQLWQMESFFAKYPQAGAGEKPREQVLETVKNNIEWLKQHRNTIREWFFNLLESG
Open
Disease
Hypertension
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

The ENPEP gene encodes Glutamyl Aminopeptidase (EAP), which, as a type II integral membrane protein, possesses significant physiological functions. Its structural hallmark includes an extracellular zinc-binding domain crucial for its catalytic activity. The primary function of EAP in the body is to cleave the N-terminal aspartate (Asp) from angiotensin II, playing vital roles in regulating blood pressure, angiogenesis, immune response, and tumor development.

Structure and Function of the ENPEP Gene

The ENPEP gene is situated on a particular chromosome in humans and encodes the membrane protein Glutamyl Aminopeptidase, which is present on the cell surface, with an extracellular catalytic domain and a transmembrane domain. The enzyme primarily catalyzes the cleavage of acidic amino acids in peptide chains, namely the N-terminal aspartate of Angiotensin II (AngII). Angiotensin II is an essential bioactive peptide significantly engaged in the regulation of blood pressure and fluid homeostasis. ENPEP is crucial in blood pressure management by converting AngII to Angiotensin III (AngIII), hence modifying its physiological effects.

Figure 1 depicts the chromosomal localization of the human ENPEP gene.Figure 1. Chromosomal localization of human ENPEP. (Wang J, et al., 1998)

In addition to its role in blood pressure regulation, ENPEP is closely linked to various biological processes including angiogenesis, cell proliferation, and immune response. Notably, its role in the tumor microenvironment is garnering significant attention. Studies suggest that ENPEP not only affects tumor growth and metastasis but also may be involved in tumor immune evasion. These effects are manifested through its regulation of tumor angiogenesis, the invasiveness of tumor cells, and immune responses, making ENPEP an important target in cancer research.

ENPEP and Hypertension

ENPEP plays a crucial role in the development and maintenance of hypertension, a globally prevalent disease impacting cardiovascular health. Through its action in the brain, ENPEP regulates the metabolism of angiotensin II. Angiotensin II (AngII) is known to trigger hypertension, and ENPEP's conversion of AngII to AngIII enhances AngIII's hypertensive effect.

Experimental studies indicate that excessive ENPEP activity in the brain's angiotensin system increases Angiotensin III production, thereby elevating blood pressure. Especially in animal models, inhibiting ENPEP activity effectively reduces blood pressure, providing new therapeutic insights for hypertension. Targeting ENPEP may become a focus for new antihypertensive drugs, potentially avoiding the side effects associated with traditional medications such as ACE inhibitors and Angiotensin II receptor blockers (ARBs), while improving treatment efficacy.

Moreover, ENPEP is intimately involved with the central nervous system's angiotensin system. Studies suggest that ENPEP, by converting AngII to AngIII, directly influences the hypothalamic regulation of blood pressure. This process involves interactions among multiple neurohormones and receptors, where ENPEP inhibition can reduce blood pressure by preventing any production. Therefore, ENPEP's role extends beyond the peripheral vascular system, offering new directions for antihypertensive therapy through its central nervous system regulatory actions.

ENPEP and Its Relationship with Tumors

In recent years, the role of ENPEP in cancer research has drawn increasing attention. Tumor growth and metastasis require adequate vascular supply, and ENPEP influences tumor angiogenesis by modulating angiotensin levels. Studies have found high ENPEP expression in various cancers such as breast cancer, renal cancer, and leukemia, with expression levels closely related to tumor invasiveness and metastatic potential.

ENPEP facilitates tumor expansion by influencing angiogenesis in the tumor microenvironment, providing the necessary nutrients and oxygen for tumor growth. Overactive ENPEP may enable tumor cells to more easily breach vascular barriers and metastasize to other organs. Additionally, ENPEP may promote tumor immune evasion by affecting immune cell functions. ENPEP can modulate immune cell infiltration and activity, aiding tumor survival and progression under immune surveillance.

Clinically, ENPEP expression levels are closely associated with cancer patient prognosis. For instance, in colorectal cancer patients, ENPEP expression is positively correlated with survival rates, making ENPEP an important prognostic marker in cancer. Additionally, ENPEP expression is linked to the effectiveness of cancer immunotherapy, and targeting ENPEP treatment strategies may enhance immunotherapy efficacy.

ENPEP's Association with SARS-CoV-2

Following the outbreak of the COVID-19 pandemic, ENPEP gained attention as a potential candidate receptor for SARS-CoV-2. While ACE2 is considered the primary receptor for SARS-CoV-2, studies have validated ENPEP's role as an auxiliary receptor. ENPEP may facilitate viral entry into host cells by binding with the virus, particularly in cells or tissues where ACE2 expression is low, promoting the infection process.

This finding provides new research avenues for COVID-19 prevention and treatment. Targeting ENPEP strategies could help block viral invasion and reduce infection risk. Interventions targeting ENPEP may offer new drug targets for antiviral treatment, especially under rapid viral mutation conditions, making targeting ENPEP an effective adjunctive therapy approach.

ENPEP and Immune System Regulation

ENPEP plays crucial roles not only in hypertension and cancer but also within the immune system. Research suggests that ENPEP is involved in the differentiation of B cells, particularly in the transition between mature and immature B cells, where ENPEP expression is upregulated. ENPEP expression is regulated by cytokines like IL-7, highlighting its important role in immune response, especially in early immune system development.

Moreover, ENPEP's role in immune response is similar to its function in the tumor microenvironment, potentially influencing tumor immune evasion mechanisms by affecting immune cell function. ENPEP's regulation of immune cells offers new directions for cancer immunotherapy. Targeting ENPEP strategies in tumor immunotherapy may promote tumor clearance by enhancing immune cell responses.

References:

  1. Wang A, Chu H, et al. ENPEP as a potential predictor of immune checkpoint inhibitor efficacy. Cancer Med. 2022 Feb;11(3):880-887.
  2. Reaux A, Iturrioz X, et al. Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem Soc Trans. 2000;28(4):435-40.
  3. Wang J, Lin Q, Wu Q, Cooper MD. The enigmatic role of glutamyl aminopeptidase (BP-1/6C3 antigen) in immune system development. Immunol Rev. 1998 Feb;161:71-7.
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