Insulin regulated aminopeptidase

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and oxytocin. The distinct configuration of the GAMEN motif in IRAP generates additional space around residues 3 and 4 of the bound linear peptide, which could be used for the accommodation of bulkier side chains, possibly affording a broader selectivity for peptides. The atomic interactions between a ligand and IRAP can promote conformational closing. The open conformation is responsible for initial substrate capture, which can induce further closing that enhances interactions and facilitates catalysis. The IRAP/ligand-bound structure has significant differences compared to the “open” structure and IRAP/peptide structure. Domain IV was found juxtaposed against domains I/II, resulting in the full exclusion of the internal cavity from the external solvent. Recently, the crystal structure of IRAP with a macrocyclic peptide inhibitor was solved, identifying several key features of the inhibition mechanism. The close juxtaposition of the GAMEN loop on the bound inhibitor does not allow space for the motion of water molecules to interact with the ionized carboxylate of the active site residue Glu (Glu465). A synergy of two mechanisms, stabilization of closed conformation and exclusion of catalytic water by the tightly juxtaposed GAMEN loop was proposed as the mechanism of inhibition. Moreover, M1 aminopeptidases use a tyrosine residue in the active site to stabilize the transition state. In the case of IRAP, the catalytic Tyr549 is found in different orientations in the open and closed conformations. For example, in the case of phosphinic pseudopeptide inhibitors, which mimic the transition state of peptide substrates, Tyr549 changes orientation upon ligand binding to interact with one of the oxygen atoms of the phosphinic group, which is equivalent to the oxygen atoms of the substrate in the transition state.

1586: 28: 1647: 1288:) in other immune cell types. In T cells, IRAP regulates the trafficking of TCD3ζ chains, that are recruited to IRAP intracellular vesicles, as well as endosomal signalling by the TCR complex. IRAP depletion increases the TCR levels at the cell surface which, however, display defective signalling. Other studies demonstrated that IRAP regulates Toll-like receptor 9 (TLR9) activation by delaying maturation of TLR9-containing endosomes to lysosomes and limiting, as a consequence, TLR9 cleavage and activation. Finally, IRAP has an important role in the secretion of the proinflammatory cytokines TNFa and IL-6 by 1409: 313: 290: 187: 212: 3131: 1391:

intra-endosomal domain harbours the Zn-binding motif known as HEXXH(X)18E, as well as the exopeptidase motif GAMEN. These two motifs are also present in ERAP1 and ERAP2 and are shared among all members of the M1 family of aminopeptidases. The C-terminal domain has been crystallized as a dimer, each monomer consisting of four continuous domains and forming a closed hollow structure with the active site at its center. Domain I (residues 171–365) forms an extensive

319: 218: 1556:

Benzopyran-based compounds were identified in a virtual screening against IRAP in 2008 and interact with the zinc cation of the catalytic site. All compounds showed specificity towards IRAP against the other aminopeptidases with a nanomolar affinity, while HFI-419 displayed the highest potency (Ki =

1436:

IRAP1 uses a catalytic mechanism like the one proposed for LTA4 hydrolase. It adopts a thermolysin-like fold and has been crystallized in two distinct conformations, an open and a closed one (Figure 1). IRAP is the only documented M1 aminopeptidase that can cleave cyclic peptides such as vasopressin

1372:

risk. IRAP's precise role in these conditions remains unknown but given its involvement in activation of adaptive and innate immune responses, the renin-angiotensin system (RAS) and glucose metabolism, these genetic variants may have pleiotropic impacts on immune, circulatory, and metabolic systems.

1823:

Bernstein HG, Müller S, Dobrowolny H, Wolke C, Lendeckel U, Bukowska A, et al. (August 2017). "Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in

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with a Zn ion at its center. The catalytic Zn ion is coordinated by His464, His468, and Glu487 of HEXXH(X)18-E zinc-binding motif. Domain III (residues 616–704) adopts a β-sandwich fold consisting of three and four-stranded β-sheets and forms a bridge between domains II and IV. Domain IV (residues

1489:

trafficking and translocation to the phagocytic cup is regulated by immune receptors, such as TLR4 and FcgRs. Finally, IRAP has been proposed to interact with major histocompatibility complexes class-I (MHC-I) in specialized endosomes in DCs. There it exhibits roles in antigen cross-presentation.

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The human IRAP gene encodes a type II transmembrane protein that consists of three distinct domains: an N-terminal cytoplasmic domain containing 109 amino acids, a transmembrane domain of 23 amino acids, and an intraluminal (or extracellular) domain composed of 893 amino acids. The C-terminal

1488:

Under inflammatory conditions its role in GSV trafficking in adipocytes is regulated by the TNFa protein via glycosylation. Recently, its interaction with the z chain of the TCR (T-cell receptor) and the Lck kinase in T lymphocytes was discovered. In dendritic cells, IRAP-dependent vesicle

1238:

which has been shown to have a neuroprotective effect. This evidence has prompted research on developing analogues with high IRAP selectivity, that show potential in memory enhancement, vascular regulation, and anticonvulsive/antiepileptogenic effects. These analogues were studied for

1243:, demonstrating improved stability and brain penetration, strong binding affinity to the targeted receptors, and positive effects on cognitive function and neuroprotection in animal models. IRAP inhibitors have also been found to counteract acetylcholine-induced vasoconstriction 54: 1415:

Crystal structures of IRAP in different conformations. The four domains are depicted in green, violet, cyan and orange for Domain I, II, III and IV respectively. The zinc atom is shown as a red sphere and the compounds co-crystallized with the enzyme are shown in yellow.

2567:

Mpakali A, Saridakis E, Harlos K, Zhao Y, Papakyriakou A, Kokkala P, et al. (September 2015). "Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing".

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Kokkala P, Mpakali A, Mauvais FX, Papakyriakou A, Daskalaki I, Petropoulou I, et al. (October 2016). "Optimization and Structure-Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides".

1152:. It is also known as oxytocinase, leucyl and cystinyl aminopeptidase, placental leucine aminopeptidase (P-LAP), cystinyl aminopeptidase (CAP), and vasopressinase. IRAP is expressed in different cell types, mainly located in specialized regulated 1259:

binding. In contrast to ERAP1 and ERAP2, there is no evidence of IRAP-mediated trimming of antigenic peptides in the endoplasmic reticulum for the MHC-I presentation through the direct pathway. On the other hand, IRAP has a primary function in

2879:

Andersson H, Demaegdt H, Vauquelin G, Lindeberg G, Karlén A, Hallberg M, et al. (November 2010). "Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)".

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IRAP stabilizes the particular type of regulated early endosomes it is located in. The stability of these endosomes is essential for the cross-presentation pathway in dendritic cells, and regulates several endosomal signaling pathways

1231:. Furthermore, an alteration in neuropeptide levels, due to IRAP deregulation, seems to be one of the mechanisms affecting learning and cognition processes, highlighting a fundamental function of IRAP also in memory disorders. 2252:

Weimershaus M, Carvalho C, Rignault R, Waeckel-Enee E, Dussiot M, van Endert P, et al. (June 2023). "Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi".

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IRAP plays an important role in the regulation of the immune system. Similarly to ERAP1 and ERAP2, IRAP is able to trim the N-terminal of antigenic peptides, reducing their length to 8-10 amino acids, the optimal length for

1643:= 5.8 μM) and according to docking studies, the inhibitor acts in a binding pocket close to the GAMEN loop without interacting with the zing atom, leading to uncompetitive inhibition, confirmed later on by kinetic studies. 1638:

During a screening process in 2016, a spiro-oxindole dihydroquinazoline compound was identified as one of the most potent hits towards IRAP. This kind of compounds shows a high specificity for IRAP against APN (Compound 8

1620:

recognized the ability of aryl sulfonamides to inhibit IRAP after screening a library of 10,500 drug-like compounds. After further optimization, compound 7 was developed displaying micromolar affinity towards IRAP

1497:

Therapeutic approaches for IRAP regulation rely on the development of peptidomimetics and small molecule inhibitors. The most explored classes of inhibitors for IRAP are the catalytic or the allosteric site ones.

2107:

El-Hawli A, Qaradakhi T, Hayes A, Rybalka E, Smith R, Caprnda M, et al. (February 2017). "IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model".

2036:

Nikolaou A, Van den Eynde I, Tourwé D, Vauquelin G, Tóth G, Mallareddy JR, et al. (February 2013). "IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase".

2527:

Hermans SJ, Ascher DB, Hancock NC, Holien JK, Michell BJ, Chai SY, et al. (February 2015). "Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides".

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IRAP has been reported to interact through its cytoplasmic domain with various proteins involved in vesicular trafficking, organelle tethering, and cytoskeleton remodeling. These proteins include

1604:

A novel family of zinc-targeting diaminobenzoic acid (DABA) compounds were rationally designed bearing natural and unnatural aminoacid moieties, with micromolar potency for IRAP (compound 6, IC

1184:, impairs glucose uptake by blocking the glucose transporter type 4 (Glut4) trafficking at the cell membrane. This evidence underlies a central function of the aminopeptidase in this disease. 2288:

Venema WJ, Hiddingh S, van Loosdregt J, Bowes J, Balliu B, de Boer JH, et al. (January 2024). "A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs".

1453:, and p115, which regulate Golgi vesicle trafficking; vimentin, an intermediate cytoskeleton filament; and the actin remodeling protein FHOS. Furthermore, IRAP was found to associate with 2146:

Saveanu L, Carroll O, Weimershaus M, Guermonprez P, Firat E, Lindo V, et al. (July 2009). "IRAP identifies an endosomal compartment required for MHC class I cross-presentation".

1585: 1788:

Herbst JJ, Ross SA, Scott HM, Bobin SA, Morris NJ, Lienhard GE, et al. (April 1997). "Insulin stimulates cell surface aminopeptidase activity toward vasopressin in adipocytes".

1400:

705–1025) consists of α-helices and assemble in a “bowl-like” shape. The active site of IRAP is capped by domain IV to form a large, mostly enclosed cavity adjacent to the Zn ion.

1472:

Apart from its association with intracellular trafficking proteins, IRAP has also been also observed to interact with proteins present in Glut4 storage vesicles (GSVs), such as

1859:

Yeatman HR, Albiston AL, Burns P, Chai SY (December 2016). "Forebrain neurone-specific deletion of insulin-regulated aminopeptidase causes age related deficits in memory".

326: 225: 2397:

Cheng H, Li Y, Zuo XB, Tang HY, Tang XF, Gao JP, et al. (February 2014). "Identification of a missense variant in LNPEP that confers psoriasis risk".

2072:

Wright JW, Kawas LH, Harding JW (February 2015). "The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases".

853: 148: 2217:

Babdor J, Descamps D, Adiko AC, Tohmé M, Maschalidi S, Evnouchidou I, et al. (May 2017). "IRAP endosomes restrict TLR9 activation and signaling".

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Crystal structure with a macrocyclic peptide inhibitor (PDB ID 6YDX). The enzyme is found in a closed conformation upon binding of the inhibitor.

27: 1735: 1515:

published a macrocyclized version of an AngIV derivative (Compound 1) which confers metabolic stability together with high affinity for IRAP (

2348:

Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. (Wellcome Trust Case Control Consortium) (November 2007).

2841:

Lukaszuk A, Demaegdt H, Szemenyei E, Tóth G, Tymecka D, Misicka A, et al. (April 2008). "Beta-homo-amino acid scan of angiotensin IV".

1717: 1537:= 27.5 nM) and displayed around 200-fold selectivity over APN. Further structural modifications on the AngIV-based inhibitors from Anderson 3191: 1646: 312: 2605:"Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity" 1395:

with a seven-stranded β-saddle flanked on either side by three- and four-stranded β-sheets. Domain II (residues 366–615) contains the

1068: 1061: 289: 2800: 1995: 1292:. In the absence of IRAP, the trafficking of vesicles containing TNFα and IL-6 from the Golgi to the plasma membrane is impaired. 1408: 1704: 1683: 1596:

Crystal structure of IRAP co-crystallized with macrocycle HA08 in two binding poses. Adapted and recreated from PDB code 6YDX.

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are intronic variants that are part of an extended haplotype that functions as a transcriptional enhancer of the adjacent gene

1945:"AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway" 1247:, highlighting IRAP's role in modulating vascular function. IRAP deletion reduces susceptibility to pentylenetetrazol-induced 1326: 1700: 211: 186: 51: 2917:"Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase" 1679: 1235: 3165: 3081:"Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors" 2434:"P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling" 128: 1364:

of which the most common rs2303138, leading to an amino acid substitution (Ala763Thr), has been related to

325: 224: 2801:"Binding of "AT4 receptor" ligands to insulin regulated aminopeptidase (IRAP) in intact Chinese hamster ovary cells" 1996:"Binding of "AT4 receptor" ligands to insulin regulated aminopeptidase (IRAP) in intact Chinese hamster ovary cells" 1349:

shows low tolerance to protein-truncating genetic variation and contains few loss-of-function variants in its gene.

2192:

Baldari CT, Onnis A (2021). IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses.

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Crystal structure with a linear peptide analogue (PDB ID 4z7i). The enzyme is found in a semi-closed conformation,

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Two other common missense variants rs41276279 (p.Val373Ile) and rs11746232 (p.Ile963Val) moderately correlate with

1541:

led to optimized macrocycle HA08 (available crystal structure within IRAP, Figure 2) with excellent IRAP potency (

318: 217: 2325:

Faculty Opinions recommendation of The mutational constraint spectrum quantified from variation in 141,456 humans

1240: 3206: 1600:

2D chemical structure of HA08. The dotted lines depict the interaction of the ligand’s C-terminal with Arg 929.

898: 136: 2699:"The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells" 3158: 1264:. Here, the aminopeptidase trims cross-presented peptides in a specific endosomal compartment, described in 879: 1753:

Keller SR (June 2004). "Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes".

2995:

Smith RJ, Bryant RG (October 1975). "Metal substitutions incarbonic anhydrase: a halide ion probe study".

1369: 2604: 2647:"Structural Basis of Inhibition of Insulin-Regulated Aminopeptidase by a Macrocyclic Peptidic Inhibitor" 1896:"Brain angiotensin II and angiotensin IV receptors as potential Alzheimer's disease therapeutic targets" 1281: 1133: 2485:"Cloning and characterization of a novel insulin-regulated membrane aminopeptidase from Glut4 vesicles" 3032:"Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides" 2155: 1277: 200: 115: 1511:

The first reported IRAP inhibitors were designed as angiotensin IV (AngIV) analogs. In 2006, Axén

3196: 2350:"Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants" 1573:

in 2016 were non-selective ERAP inhibitors, DG026 displayed a nanomolar affinity towards IRAP (IC

1377:

gene expression levels (reference to gtexportal.org) but have not been linked to disease so far.

1313:

This gene is ~75 kb in length and consists of 18 exons and 17 introns. According to ensembl.org,

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antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent

160: 3130: 1044: 1023: 1019: 993: 972: 968: 2697:

Descamps D, Evnouchidou I, Caillens V, Drajac C, Riffault S, van Endert P, et al. (2020).

3110: 3061: 3012: 2977: 2938: 2897: 2858: 2823: 2781: 2730: 2676: 2624: 2585: 2544: 2506: 2465: 2414: 2379: 2305: 2270: 2234: 2171: 2125: 2089: 2054: 2018: 1976: 1925: 1876: 1841: 1805: 1770: 1361: 1223:. Most of them have primary functions in the development of neurological disorders, including 108: 44: 3142: 2603:

Mpakali A, Saridakis E, Harlos K, Zhao Y, Kokkala P, Georgiadis D, et al. (April 2017).

3201: 3100: 3092: 3051: 3043: 3004: 2969: 2928: 2889: 2850: 2815: 2799:

Demaegdt H, Gard P, De Backer JP, Lukaszuk A, Szemenyei E, Tóth G, et al. (June 2011).

2771: 2761: 2720: 2710: 2666: 2658: 2616: 2577: 2536: 2496: 2455: 2445: 2406: 2369: 2361: 2328: 2297: 2262: 2226: 2197: 2163: 2117: 2081: 2046: 2010: 1994:

Demaegdt H, Gard P, De Backer JP, Lukaszuk A, Szemenyei E, Tóth G, et al. (June 2011).

1966: 1956: 1915: 1907: 1868: 1833: 1797: 1762: 405: 336: 280: 235: 119:, CAP, IRAP, P-LAP, PLAP, leucyl/cystinyl aminopeptidase, leucyl and cystinyl aminopeptidase 156: 2750:"The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review" 1273: 1228: 1196: 1181: 380: 2645:

Mpakali A, Saridakis E, Giastas P, Maben Z, Stern LJ, Larhed M, et al. (July 2020).

2432:

Shibata K, Kajiyama H, Ino K, Nawa A, Nomura S, Mizutani S, et al. (January 2007).

2159: 3105: 3080: 3056: 3031: 3030:

Vanga SR, Sävmarker J, Ng L, Larhed M, Hallberg M, Åqvist J, et al. (April 2018).

2776: 2749: 2725: 2698: 2671: 2646: 2460: 2433: 2374: 2349: 1971: 1944: 1920: 1895: 1396: 1329:

have been associated with diseases. The vast majority of single nucleotide variants in

1265: 1180:

receptor signaling. Alteration of IRAP recruitment at the cell surface, as observed in

1156:

that can be recruited to the cell surface upon cell type-specific receptor activation.

1141: 3079:

Engen K, Vanga SR, Lundbäck T, Agalo F, Konda V, Jensen AJ, et al. (March 2020).

2915:

Albiston AL, Morton CJ, Ng HL, Pham V, Yeatman HR, Ye S, et al. (December 2008).

2501: 2484: 1164:

IRAP functions depend on the cell type and extracellular environment. For example, in

768: 763: 758: 753: 748: 743: 738: 733: 728: 723: 718: 702: 697: 692: 687: 682: 677: 672: 667: 662: 657: 652: 636: 631: 626: 621: 616: 611: 606: 601: 596: 3185: 3008: 1392: 1285: 1224: 583: 2085: 1801: 140: 2662: 1469:. This suggests that IRAP plays a role in recruiting AS160 to endocytic membranes. 1216: 1192: 398: 177: 3047: 2333: 2202: 1234:

In the brain, IRAP is the major receptor of Ang IV, an essential component of the

2973: 2620: 2121: 2050: 164: 1740:

National Center for Biotechnology Information, U.S. National Library of Medicine

1722:

National Center for Biotechnology Information, U.S. National Library of Medicine

1450: 1256: 1220: 1208: 1200: 1169: 1137: 1911: 481: 2819: 2766: 2715: 2301: 2266: 2014: 1872: 1837: 1473: 1212: 1204: 1187:

IRAP cleaves several hormones, vasoactive peptides, and neuropeptides such as

297: 194: 144: 2581: 1961: 3138: 2167: 1446: 1365: 1289: 1165: 798: 541: 419: 364: 351: 263: 250: 152: 3114: 3096: 3065: 2981: 2942: 2901: 2862: 2827: 2785: 2734: 2680: 2628: 2589: 2548: 2469: 2450: 2418: 2383: 2309: 2274: 2238: 2175: 2129: 2093: 2058: 2022: 1980: 1929: 1880: 1845: 1774: 1569:

Although most of the phosphinic pseudopeptide analogs disclosed by Kokkala

2540: 2510: 2483:

Keller SR, Scott HM, Mastick CC, Aebersold R, Lienhard GE (October 1995).

1809: 1108: 1103: 2933: 2916: 2410: 1188: 1153: 1092: 943: 924: 2748:

Georgiadis D, Ziotopoulou A, Kaloumenou E, Lelis A, Papasava A (2020).

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expression. In fact, compared to its M1- aminopeptidase family members

1317:

has 5 transcripts but only one major expressed isoform (NM_005575.3).

1248: 1177: 1121: 910: 865: 2893: 2854: 2110:

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie

85: 81: 77: 73: 1454: 1124:

that in humans is encoded by the leucyl and cystinyl aminopeptidase (

1076: 820: 3016: 2230: 1176:

storage vesicles (GSV) and regulates GSV trafficking in response to

1645: 1548:= 3.3 nM) and selectivity over APN, but poor metabolic stability. 1481: 1466: 1462: 1458: 1268:, before their loading on IRAP-associated MHC class I molecules. 1251:

in mice, suggesting its potential as epilepsy therapeutic target.

1173: 1149: 1145: 1309:(leucyl and cystinyl aminopeptidase) gene, located on chromosome 783: 779: 1477: 1325:

Among the different genetic variants identified so far, several

1129: 132: 1943:

Sun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y (November 2021).

1420:

Crystal structure in the closed conformation (PDB ID 4P8Q),

1424:

Crystal structure in the open conformation (PDB ID 5C97),

1826:

European Archives of Psychiatry and Clinical Neuroscience

1653:. Representative examples of reported IRAP inhibitors. IC 1608:= 2.1 μM) and moderate selectivity over ERAP1 and ERAP2. 388: 3146: 1457:, a Rab GTPase activating protein (GAP) specific for 553: 2997:

Biochemical and Biophysical Research Communications

1037: 1012: 986: 961: 1696: 1694: 1692: 1675: 1673: 1671: 2874: 2872: 335: 234: 2692: 2690: 2954: 2952: 2640: 2638: 2562: 2560: 2558: 2522: 2520: 2187: 2185: 2141: 2139: 2255:The Journal of Allergy and Clinical Immunology 1701:GRCm38: Ensembl release 89: ENSMUSG00000023845 3166: 1120:Insulin regulated aminopeptidase (IRAP) is a 8: 1680:GRCh38: Ensembl release 89: ENSG00000113441 1522:= 25.8 nM). Under a similar scope Lukaszuk 3173: 3159: 794: 579: 376: 275: 172: 62: 3104: 3055: 2932: 2775: 2765: 2724: 2714: 2670: 2500: 2459: 2449: 2373: 2332: 2201: 1970: 1960: 1919: 2399:The Journal of Investigative Dermatology 1755:Biological & Pharmaceutical Bulletin 1584: 1407: 1667: 1493:Therapeutic approaches and pharmacology 17: 1657:value measured on long-peptide assay. 673:integral component of plasma membrane 340: 301: 296: 239: 198: 193: 7: 3127: 3125: 2808:Molecular and Cellular Endocrinology 2003:Molecular and Cellular Endocrinology 1577:= 32 nM) with improved selectivity. 2489:The Journal of Biological Chemistry 1861:Neurobiology of Learning and Memory 1360:has five common (>1% in GnomAD) 3145:. You can help Knowledge (XXG) by 2703:Frontiers in Molecular Biosciences 1790:The American Journal of Physiology 1634:Spiro-oxindole dihydroquinazolines 1034: 1009: 983: 958: 934: 915: 889: 870: 844: 825: 678:intracellular anatomical structure 558: 476: 414: 393: 14: 1894:Royea J, Hamel E (October 2020). 3129: 2039:European Journal of Pharmacology 1557:0.48 μM) and was also tested in 1530:which was able to inhibit IRAP ( 1296:Genetics / Clinical significance 719:SMAD protein signal transduction 324: 317: 311: 288: 223: 216: 210: 185: 26: 2651:ACS Medicinal Chemistry Letters 2194:Faculty Opinions Recommendation 2086:10.1016/j.pneurobio.2014.11.004 1802:10.1152/ajpendo.1997.272.4.e600 1629:IRAP allosteric site inhibitors 1172:, IRAP is a major component of 693:perinuclear region of cytoplasm 2962:Journal of Medicinal Chemistry 2882:Journal of Medicinal Chemistry 2843:Journal of Medicinal Chemistry 2663:10.1021/acsmedchemlett.0c00172 2609:Journal of Medicinal Chemistry 1561:bioassays of memory function. 1502:IRAP catalytic site inhibitors 653:integral component of membrane 627:metalloaminopeptidase activity 542:More reference expression data 1: 3048:10.1021/acsomega.8b00595.s003 2502:10.1016/s0021-9258(17)45857-1 2334:10.3410/f.738024093.793575805 2203:10.3410/f.738064950.793586214 309: 208: 3009:10.1016/0006-291x(75)90498-2 2974:10.1021/acs.jmedchem.6b01031 2621:10.1021/acs.jmedchem.6b01890 2122:10.1016/j.biopha.2016.11.142 2051:10.1016/j.ejphar.2013.01.026 749:regulation of blood pressure 703:cytoplasmic vesicle membrane 3192:Genes on human chromosome 5 450:superficial temporal artery 3223: 3124: 1912:10.1007/s11357-020-00231-y 1327:single nucleotide variants 1241:neurodegenerative diseases 734:protein polyubiquitination 500:superior cervical ganglion 2820:10.1016/j.mce.2011.03.005 2767:10.3389/fphar.2020.585838 2754:Frontiers in Pharmacology 2716:10.3389/fmolb.2020.583556 2302:10.1101/2023.03.03.530973 2267:10.1101/2022.01.21.477149 2015:10.1016/j.mce.2011.03.005 1873:10.1016/j.nlm.2016.09.017 1838:10.1007/s00406-016-0757-7 1736:"Mouse PubMed Reference:" 1718:"Human PubMed Reference:" 1565:Phosphinic pseudopeptides 1107: 1102: 1098: 1091: 1075: 1056: 1041: 1016: 1005: 990: 965: 954: 941: 937: 922: 918: 909: 896: 892: 877: 873: 864: 851: 847: 832: 828: 819: 804: 797: 793: 777: 769:peptide catabolic process 754:protein catabolic process 622:metallopeptidase activity 582: 578: 566: 561: 552: 539: 488: 479: 446:epithelium of nasopharynx 426: 417: 387: 379: 375: 358: 345: 308: 287: 278: 274: 257: 244: 207: 184: 175: 171: 126: 123: 113: 106: 101: 70: 65: 48: 43: 38: 34: 25: 20: 2582:10.4049/jimmunol.1501103 2074:Progress in Neurobiology 1962:10.3390/brainsci11111487 1824:chronic schizophrenia". 1236:renin-angiotensin system 1069:Chr 17: 17.74 – 17.85 Mb 2168:10.1126/science.1172845 1526:produced compound AL-11 1305:IRAP is encoded by the 1062:Chr 5: 96.94 – 97.04 Mb 617:aminopeptidase activity 3097:10.1002/open.201900344 2451:10.1186/1471-2407-7-15 1658: 1601: 1433: 1370:ankylosing spondylitis 1337:but does not regulate 1213:Met-and Leu-enkephalin 512:mesenteric lymph nodes 2570:Journal of Immunology 1796:(4 Pt 1): E600–E606. 1649: 1588: 1411: 1381:Structure / Mechanism 1136:which belongs to the 1134:transmembrane protein 759:membrane organization 524:stroma of bone marrow 462:middle temporal gyrus 303:Chromosome 17 (mouse) 2934:10.1096/fj.08-112227 2411:10.1038/jid.2013.317 1132:. IRAP is a type II 698:early endosome lumen 683:extracellular region 528:skin of external ear 201:Chromosome 5 (human) 66:List of PDB id codes 39:Available structures 2541:10.2210/pdb4p8q/pdb 2495:(40): 23612–23618. 2261:(6): 1595–1608.e6. 2160:2009Sci...325..213S 1353:Disease association 1209:arginin vasopressin 1160:Biology / Functions 764:signal transduction 729:cell-cell signaling 458:germinal epithelium 2366:10.1038/ng.2007.17 1767:10.1248/bpb.27.761 1659: 1602: 1434: 1262:cross-presentation 899:ENSMUSG00000023845 712:Biological process 688:lysosomal membrane 646:Cellular component 632:hydrolase activity 607:peptidase activity 590:Molecular function 3154: 3153: 2968:(19): 9107–9123. 2927:(12): 4209–4217. 2894:10.1021/jm100793t 2888:(22): 8059–8071. 2855:10.1021/jm701490g 2323:Mulder N (2020). 2219:Nature Immunology 2154:(5937): 213–217. 1612:Aryl sulfonamides 1362:missense variants 1118: 1117: 1114: 1113: 1087: 1086: 1052: 1051: 1031: 1030: 1001: 1000: 980: 979: 950: 949: 931: 930: 905: 904: 886: 885: 860: 859: 841: 840: 789: 788: 602:metal ion binding 574: 573: 570: 569: 548: 547: 535: 534: 473: 472: 371: 370: 270: 269: 165:LNPEP - orthologs 97: 96: 93: 92: 49:Ortholog search: 3214: 3175: 3168: 3161: 3133: 3126: 3119: 3118: 3108: 3076: 3070: 3069: 3059: 3042:(4): 4509–4521. 3027: 3021: 3020: 3003:(4): 1281–1286. 2992: 2986: 2985: 2956: 2947: 2946: 2936: 2912: 2906: 2905: 2876: 2867: 2866: 2849:(7): 2291–2296. 2838: 2832: 2831: 2805: 2796: 2790: 2789: 2779: 2769: 2745: 2739: 2738: 2728: 2718: 2694: 2685: 2684: 2674: 2657:(7): 1429–1434. 2642: 2633: 2632: 2615:(7): 2963–2972. 2600: 2594: 2593: 2576:(6): 2842–2851. 2564: 2553: 2552: 2524: 2515: 2514: 2504: 2480: 2474: 2473: 2463: 2453: 2429: 2423: 2422: 2394: 2388: 2387: 2377: 2345: 2339: 2338: 2336: 2320: 2314: 2313: 2285: 2279: 2278: 2249: 2243: 2242: 2214: 2208: 2207: 2205: 2189: 2180: 2179: 2143: 2134: 2133: 2104: 2098: 2097: 2069: 2063: 2062: 2033: 2027: 2026: 2000: 1991: 1985: 1984: 1974: 1964: 1940: 1934: 1933: 1923: 1906:(5): 1237–1256. 1891: 1885: 1884: 1856: 1850: 1849: 1820: 1814: 1813: 1785: 1779: 1778: 1750: 1744: 1743: 1732: 1726: 1725: 1714: 1708: 1698: 1687: 1677: 1581:DABA derivatives 1229:memory disorders 1140:subfamily of M1 1100: 1099: 1071: 1064: 1047: 1035: 1026: 1010: 1006:RefSeq (protein) 996: 984: 975: 959: 935: 916: 890: 871: 845: 826: 795: 724:female pregnancy 637:zinc ion binding 580: 559: 544: 484: 482:Top expressed in 477: 434:Brodmann area 23 422: 420:Top expressed in 415: 394: 377: 367: 354: 343: 328: 321: 315: 304: 292: 276: 266: 253: 242: 227: 220: 214: 203: 189: 173: 167: 118: 111: 88: 63: 57: 36: 35: 30: 18: 3222: 3221: 3217: 3216: 3215: 3213: 3212: 3211: 3207:Hydrolase stubs 3182: 3181: 3180: 3179: 3123: 3122: 3078: 3077: 3073: 3029: 3028: 3024: 2994: 2993: 2989: 2958: 2957: 2950: 2914: 2913: 2909: 2878: 2877: 2870: 2840: 2839: 2835: 2803: 2798: 2797: 2793: 2747: 2746: 2742: 2696: 2695: 2688: 2644: 2643: 2636: 2602: 2601: 2597: 2566: 2565: 2556: 2529:Protein Science 2526: 2525: 2518: 2482: 2481: 2477: 2431: 2430: 2426: 2396: 2395: 2391: 2360:(11): 1329–37. 2354:Nature Genetics 2347: 2346: 2342: 2322: 2321: 2317: 2287: 2286: 2282: 2251: 2250: 2246: 2231:10.1038/ni.3711 2216: 2215: 2211: 2191: 2190: 2183: 2145: 2144: 2137: 2106: 2105: 2101: 2071: 2070: 2066: 2045:(1–3): 93–102. 2035: 2034: 2030: 1998: 1993: 1992: 1988: 1942: 1941: 1937: 1893: 1892: 1888: 1858: 1857: 1853: 1822: 1821: 1817: 1787: 1786: 1782: 1752: 1751: 1747: 1734: 1733: 1729: 1716: 1715: 1711: 1699: 1690: 1678: 1669: 1664: 1656: 1642: 1631: 1624: 1616:In 2014, Vanga 1607: 1576: 1547: 1536: 1521: 1507:Peptidomimetics 1504: 1495: 1443: 1406: 1388: 1383: 1355: 1323: 1303: 1298: 1266:dendritic cells 1201:angiotensin III 1197:cholecystokinin 1182:type 2 diabetes 1162: 1142:aminopeptidases 1109:View/Edit Mouse 1104:View/Edit Human 1067: 1060: 1057:Location (UCSC) 1043: 1022: 1018: 992: 971: 967: 880:ENSG00000113441 773: 707: 668:plasma membrane 641: 612:protein binding 597:peptide binding 540: 531: 526: 522: 518: 514: 510: 506: 502: 498: 494: 492:ascending aorta 480: 469: 466:trabecular bone 464: 460: 456: 452: 448: 444: 442:parietal pleura 440: 436: 432: 430:visceral pleura 418: 362: 349: 342:17|17 A3.2 341: 331: 330: 329: 322: 302: 279:Gene location ( 261: 248: 240: 230: 229: 228: 221: 199: 176:Gene location ( 127: 114: 107: 72: 50: 12: 11: 5: 3220: 3218: 3210: 3209: 3204: 3199: 3194: 3184: 3183: 3178: 3177: 3170: 3163: 3155: 3152: 3151: 3134: 3121: 3120: 3091:(3): 325–337. 3071: 3022: 2987: 2948: 2907: 2868: 2833: 2814:(1–2): 34–44. 2791: 2740: 2686: 2634: 2595: 2554: 2535:(2): 190–199. 2516: 2475: 2424: 2405:(2): 359–365. 2389: 2340: 2315: 2280: 2244: 2225:(5): 509–518. 2209: 2181: 2135: 2099: 2064: 2028: 2009:(1–2): 34–44. 1986: 1949:Brain Sciences 1935: 1886: 1851: 1832:(5): 427–443. 1815: 1780: 1761:(6): 761–764. 1745: 1727: 1709: 1688: 1666: 1665: 1663: 1660: 1654: 1640: 1636: 1635: 1630: 1627: 1622: 1614: 1613: 1605: 1583: 1582: 1574: 1567: 1566: 1554: 1553: 1545: 1534: 1519: 1509: 1508: 1503: 1500: 1494: 1491: 1442: 1439: 1405: 1402: 1397:catalytic site 1387: 1384: 1382: 1379: 1354: 1351: 1322: 1319: 1302: 1299: 1297: 1294: 1205:Lys-bradykinin 1161: 1158: 1116: 1115: 1112: 1111: 1106: 1096: 1095: 1089: 1088: 1085: 1084: 1082: 1080: 1073: 1072: 1065: 1058: 1054: 1053: 1050: 1049: 1039: 1038: 1032: 1029: 1028: 1014: 1013: 1007: 1003: 1002: 999: 998: 988: 987: 981: 978: 977: 963: 962: 956: 952: 951: 948: 947: 939: 938: 932: 929: 928: 920: 919: 913: 907: 906: 903: 902: 894: 893: 887: 884: 883: 875: 874: 868: 862: 861: 858: 857: 849: 848: 842: 839: 838: 830: 829: 823: 817: 816: 811: 806: 802: 801: 791: 790: 787: 786: 775: 774: 772: 771: 766: 761: 756: 751: 746: 741: 736: 731: 726: 721: 715: 713: 709: 708: 706: 705: 700: 695: 690: 685: 680: 675: 670: 665: 660: 655: 649: 647: 643: 642: 640: 639: 634: 629: 624: 619: 614: 609: 604: 599: 593: 591: 587: 586: 576: 575: 572: 571: 568: 567: 564: 563: 556: 550: 549: 546: 545: 537: 536: 533: 532: 530: 529: 525: 521: 517: 513: 509: 505: 501: 497: 493: 489: 486: 485: 474: 471: 470: 468: 467: 463: 459: 455: 454:saphenous vein 451: 447: 443: 439: 435: 431: 427: 424: 423: 411: 410: 402: 391: 385: 384: 381:RNA expression 373: 372: 369: 368: 360: 356: 355: 347: 344: 339: 333: 332: 323: 316: 310: 306: 305: 300: 294: 293: 285: 284: 272: 271: 268: 267: 259: 255: 254: 246: 243: 238: 232: 231: 222: 215: 209: 205: 204: 197: 191: 190: 182: 181: 169: 168: 125: 121: 120: 112: 104: 103: 99: 98: 95: 94: 91: 90: 68: 67: 59: 58: 47: 41: 40: 32: 31: 23: 22: 13: 10: 9: 6: 4: 3: 2: 3219: 3208: 3205: 3203: 3200: 3198: 3195: 3193: 3190: 3189: 3187: 3176: 3171: 3169: 3164: 3162: 3157: 3156: 3150: 3148: 3144: 3141:article is a 3140: 3135: 3132: 3128: 3116: 3112: 3107: 3102: 3098: 3094: 3090: 3086: 3085:ChemistryOpen 3082: 3075: 3072: 3067: 3063: 3058: 3053: 3049: 3045: 3041: 3037: 3033: 3026: 3023: 3018: 3014: 3010: 3006: 3002: 2998: 2991: 2988: 2983: 2979: 2975: 2971: 2967: 2963: 2955: 2953: 2949: 2944: 2940: 2935: 2930: 2926: 2922: 2921:FASEB Journal 2918: 2911: 2908: 2903: 2899: 2895: 2891: 2887: 2883: 2875: 2873: 2869: 2864: 2860: 2856: 2852: 2848: 2844: 2837: 2834: 2829: 2825: 2821: 2817: 2813: 2809: 2802: 2795: 2792: 2787: 2783: 2778: 2773: 2768: 2763: 2759: 2755: 2751: 2744: 2741: 2736: 2732: 2727: 2722: 2717: 2712: 2708: 2704: 2700: 2693: 2691: 2687: 2682: 2678: 2673: 2668: 2664: 2660: 2656: 2652: 2648: 2641: 2639: 2635: 2630: 2626: 2622: 2618: 2614: 2610: 2606: 2599: 2596: 2591: 2587: 2583: 2579: 2575: 2571: 2563: 2561: 2559: 2555: 2550: 2546: 2542: 2538: 2534: 2530: 2523: 2521: 2517: 2512: 2508: 2503: 2498: 2494: 2490: 2486: 2479: 2476: 2471: 2467: 2462: 2457: 2452: 2447: 2443: 2439: 2435: 2428: 2425: 2420: 2416: 2412: 2408: 2404: 2400: 2393: 2390: 2385: 2381: 2376: 2371: 2367: 2363: 2359: 2355: 2351: 2344: 2341: 2335: 2330: 2326: 2319: 2316: 2311: 2307: 2303: 2299: 2296:(1): 100460. 2295: 2291: 2290:Cell Genomics 2284: 2281: 2276: 2272: 2268: 2264: 2260: 2256: 2248: 2245: 2240: 2236: 2232: 2228: 2224: 2220: 2213: 2210: 2204: 2199: 2195: 2188: 2186: 2182: 2177: 2173: 2169: 2165: 2161: 2157: 2153: 2149: 2142: 2140: 2136: 2131: 2127: 2123: 2119: 2115: 2111: 2103: 2100: 2095: 2091: 2087: 2083: 2079: 2075: 2068: 2065: 2060: 2056: 2052: 2048: 2044: 2040: 2032: 2029: 2024: 2020: 2016: 2012: 2008: 2004: 1997: 1990: 1987: 1982: 1978: 1973: 1968: 1963: 1958: 1954: 1950: 1946: 1939: 1936: 1931: 1927: 1922: 1917: 1913: 1909: 1905: 1901: 1897: 1890: 1887: 1882: 1878: 1874: 1870: 1866: 1862: 1855: 1852: 1847: 1843: 1839: 1835: 1831: 1827: 1819: 1816: 1811: 1807: 1803: 1799: 1795: 1791: 1784: 1781: 1776: 1772: 1768: 1764: 1760: 1756: 1749: 1746: 1741: 1737: 1731: 1728: 1723: 1719: 1713: 1710: 1706: 1702: 1697: 1695: 1693: 1689: 1685: 1681: 1676: 1674: 1672: 1668: 1661: 1652: 1648: 1644: 1633: 1632: 1628: 1626: 1619: 1611: 1610: 1609: 1599: 1595: 1591: 1587: 1580: 1579: 1578: 1572: 1564: 1563: 1562: 1560: 1551: 1550: 1549: 1544: 1540: 1533: 1529: 1525: 1518: 1514: 1506: 1505: 1501: 1499: 1492: 1490: 1487: 1484:in adipocytes 1483: 1479: 1475: 1470: 1468: 1464: 1460: 1456: 1452: 1448: 1440: 1438: 1431: 1427: 1423: 1419: 1414: 1410: 1403: 1401: 1398: 1394: 1385: 1380: 1378: 1376: 1371: 1367: 1363: 1359: 1352: 1350: 1348: 1344: 1340: 1336: 1332: 1328: 1320: 1318: 1316: 1312: 1308: 1301:Gene location 1300: 1295: 1293: 1291: 1287: 1283: 1279: 1275: 1269: 1267: 1263: 1258: 1252: 1250: 1246: 1242: 1237: 1232: 1230: 1226: 1225:schizophrenia 1222: 1218: 1214: 1210: 1206: 1202: 1198: 1194: 1190: 1185: 1183: 1179: 1175: 1171: 1167: 1159: 1157: 1155: 1151: 1147: 1143: 1139: 1135: 1131: 1127: 1123: 1110: 1105: 1101: 1097: 1094: 1090: 1083: 1081: 1078: 1074: 1070: 1066: 1063: 1059: 1055: 1048: 1046: 1040: 1036: 1033: 1027: 1025: 1021: 1015: 1011: 1008: 1004: 997: 995: 989: 985: 982: 976: 974: 970: 964: 960: 957: 955:RefSeq (mRNA) 953: 946: 945: 940: 936: 933: 927: 926: 921: 917: 914: 912: 908: 901: 900: 895: 891: 888: 882: 881: 876: 872: 869: 867: 863: 856: 855: 850: 846: 843: 837: 836: 831: 827: 824: 822: 818: 815: 812: 810: 807: 803: 800: 796: 792: 785: 781: 776: 770: 767: 765: 762: 760: 757: 755: 752: 750: 747: 745: 742: 740: 737: 735: 732: 730: 727: 725: 722: 720: 717: 716: 714: 711: 710: 704: 701: 699: 696: 694: 691: 689: 686: 684: 681: 679: 676: 674: 671: 669: 666: 664: 661: 659: 656: 654: 651: 650: 648: 645: 644: 638: 635: 633: 630: 628: 625: 623: 620: 618: 615: 613: 610: 608: 605: 603: 600: 598: 595: 594: 592: 589: 588: 585: 584:Gene ontology 581: 577: 565: 560: 557: 555: 551: 543: 538: 527: 523: 519: 516:otolith organ 515: 511: 507: 503: 499: 495: 491: 490: 487: 483: 478: 475: 465: 461: 457: 453: 449: 445: 441: 437: 433: 429: 428: 425: 421: 416: 413: 412: 409: 407: 403: 401: 400: 396: 395: 392: 390: 386: 382: 378: 374: 366: 361: 357: 353: 348: 338: 334: 327: 320: 314: 307: 299: 295: 291: 286: 282: 277: 273: 265: 260: 256: 252: 247: 237: 233: 226: 219: 213: 206: 202: 196: 192: 188: 183: 179: 174: 170: 166: 162: 158: 154: 150: 146: 142: 138: 134: 130: 122: 117: 110: 105: 100: 89: 87: 83: 79: 75: 69: 64: 61: 60: 56: 53: 46: 42: 37: 33: 29: 24: 19: 16: 3147:expanding it 3136: 3088: 3084: 3074: 3039: 3035: 3025: 3000: 2996: 2990: 2965: 2961: 2924: 2920: 2910: 2885: 2881: 2846: 2842: 2836: 2811: 2807: 2794: 2757: 2753: 2743: 2706: 2702: 2654: 2650: 2612: 2608: 2598: 2573: 2569: 2532: 2528: 2492: 2488: 2478: 2441: 2437: 2427: 2402: 2398: 2392: 2357: 2353: 2343: 2324: 2318: 2293: 2289: 2283: 2258: 2254: 2247: 2222: 2218: 2212: 2193: 2151: 2147: 2113: 2109: 2102: 2077: 2073: 2067: 2042: 2038: 2031: 2006: 2002: 1989: 1955:(11): 1487. 1952: 1948: 1938: 1903: 1899: 1889: 1864: 1860: 1854: 1829: 1825: 1818: 1793: 1789: 1783: 1758: 1754: 1748: 1739: 1730: 1721: 1712: 1650: 1637: 1617: 1615: 1603: 1597: 1593: 1589: 1570: 1568: 1558: 1555: 1542: 1538: 1531: 1527: 1523: 1516: 1512: 1510: 1496: 1485: 1471: 1455:AS160/Tbc1d4 1444: 1441:Interactions 1435: 1429: 1425: 1421: 1417: 1412: 1389: 1374: 1357: 1356: 1347:ERAP2, LNPEP 1346: 1342: 1338: 1334: 1330: 1324: 1314: 1310: 1306: 1304: 1270: 1253: 1244: 1233: 1217:neurokinin A 1193:somatostatin 1186: 1170:muscle cells 1163: 1144:, alongside 1125: 1119: 1042: 1017: 991: 966: 942: 923: 897: 878: 852: 833: 813: 808: 508:ciliary body 496:aortic valve 404: 397: 124:External IDs 71: 15: 1900:GeroScience 1867:: 174–182. 1625:= 0.8 μM). 1552:Benzopyrans 1451:tankyrase-2 1447:tankyrase-1 1257:MHC class I 1221:dynorphin A 1138:oxytocinase 744:proteolysis 363:17,845,312 350:17,741,672 262:97,037,513 249:96,935,394 102:Identifiers 3186:Categories 2760:: 585838. 2709:: 583556. 2438:BMC Cancer 2196:(Report). 1707:, May 2017 1686:, May 2017 1662:References 1393:β-sandwich 1290:mast cells 1166:adipocytes 408:(ortholog) 145:HomoloGene 3197:EC 3.4.11 3139:hydrolase 3036:ACS Omega 2444:(1): 15. 2116:: 23–26. 2080:: 26–46. 1413:Figure 1. 1404:Mechanism 1386:Structure 1366:psoriasis 1154:endosomes 1045:NP_766415 1024:NP_787116 1020:NP_005566 994:NM_172827 973:NM_005575 969:NM_175920 799:Orthologs 153:GeneCards 3115:32154052 3066:30023895 2982:27606717 2943:18716029 2902:21047126 2863:18386881 2828:21457753 2786:33071797 2735:33195428 2681:32676150 2629:28328206 2590:26259583 2549:25408552 2470:17233921 2419:23897274 2384:17952073 2310:38190099 2275:36708814 2239:28319098 2176:19498108 2130:27936390 2094:25455861 2059:23376157 2023:21457753 1981:34827486 1930:32700176 1881:27713012 1846:28035472 1775:15187412 1703:– 1682:– 1590:Figure 2 1474:sortilin 1249:seizures 1189:oxytocin 1093:Wikidata 778:Sources: 663:membrane 3202:Enzymes 3106:7050655 3057:6045421 2777:7538644 2726:7606930 2672:7357224 2511:7559527 2461:1781462 2375:2680141 2156:Bibcode 2148:Science 1972:8615599 1921:7525853 1810:9142880 1705:Ensembl 1684:Ensembl 1651:Table 1 1559:in vivo 1245:in vivo 1203:(Ang), 1178:insulin 1122:protein 911:UniProt 866:Ensembl 805:Species 784:QuickGO 658:cytosol 520:utricle 383:pattern 141:2387123 109:Aliases 3113: 3103: 3064: 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