Pathways & interactions
Aminopeptidase N-type (IPR034016)
Short name: M1_APN-typ
Overlapping homologous superfamilies
- Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase (IPR001930)
This M1 peptidase family includes eukaryotic and bacterial members: aminopeptidase N (APN; MEROPS identifier M01.001), aminopeptidase Q (APQ, laeverin; MEROPS identifier M01.026) [PMID: 17525158, PMID: 19819873], endoplasmic reticulum aminopeptidase 1 (ERAP1; MEROPS identifier M01.018) [PMID: 20531381] as well as tricorn interacting factor F3 (MEROPS identifier M01.021).
Aminopeptidase N (APN; CD13; Alanyl aminopeptidase; EC 184.108.40.206), a type II integral membrane protease, consists of a small N-terminal cytoplasmic domain, a single transmembrane domain, and a large extracellular ectodomain that contains the active site. It preferentially cleaves neutral amino acids from the N terminus of oligopeptides and is present in a variety of human tissues and cell types (leukocyte, fibroblast, endothelial and epithelial cells). APN expression is dysregulated in inflammatory diseases such as chronic pain, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyosytis and pulmonary sarcoidosis, and is enhanced in tumor cells such as melanoma, renal, prostate, pancreas, colon, gastric and thyroid cancers. It is considered a marker of differentiation since it is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs [PMID: 17346152, PMID: 21205077].
ERAP1 also known as endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), adipocyte derived leucine aminopeptidase (A-LAP) or aminopeptidase regulating tumor necrosis factor receptor I (THFRI) shedding (ARTS-1), associates with the closely related ER aminopeptidase ERAP2 (MEROPS identifier M01.024), for the final trimming of peptides within the ER for presentation by MHC class I molecules. ERAP1 is associated with ankylosing spondylitis (AS), an inflammatory arthritis that predominantly affects the spine. ERAP1 also aids in the shedding of membrane-bound cytokine receptors [PMID: 20531381].
The tricorn interacting factor F3, together with factors F1 and F2, degrades the tricorn protease products, producing free amino acids, thus completing the proteasomal degradation pathway. F3 is homologous to F2, but not F1, and shows a strong preference for glutamate in the P1' position [PMID: 15893768].
APQ, also known as laeverin, is specifically expressed in human embryo-derived extravillous trophoblasts (EVTs) that invade the uterus during early placentation [PMID: 14706636]. It cleaves the N-terminal amino acid of various peptides such as angiotensin III, endokinin C, and kisspeptin-10, all expressed in the placenta in large quantities.
APN is a receptor for coronaviruses, although the virus receptor interaction site seems to be distinct from the enzymatic site and aminopeptidase activity is not necessary for viral infection [PMID: 17346152]. Insect APNs (MEROPS identifiers M01.013 and M01.030) are also putative Cry toxin receptors. Cry1 proteins are pore-forming toxins that bind to the midgut epithelial cell membrane of susceptible insect larvae, causing extensive damage. Several different toxins, including Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ca and Cry1Fa, have been shown to bind to APNs; however, a direct role of APN in cytotoxicity has been yet to be firmly established [PMID: 21210704].
- cd09601 (M1_APN_2)