Genomes and Genes
Summary: A subclass of EXOPEPTIDASES that act on the free N terminus end of a polypeptide liberating a single amino acid residue. EC 3.4.11.
- Hinks A, Martin P, Flynn E, Eyre S, Packham J, Barton A, et al. Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis. Arthritis Res Ther. 2011;13:R12 pubmed publisher..The findings will require validation in independent JIA datasets. These results suggest distinct pathogenic pathways in these subtypes. ..
- Guerini F, Cagliani R, Forni D, Agliardi C, Caputo D, Cassinotti A, et al. A functional variant in ERAP1 predisposes to multiple sclerosis. PLoS ONE. 2012;7:e29931 pubmed publisher..Results herein support the emerging concept that a subset of master-regulatory genes underlay the pathogenesis of autoimmunity. ..
- Strange A, Capon F, Spencer C, Knight J, Weale M, Allen M, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42:985-90 pubmed publisher..Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis. ..
- Poreba M, McGowan S, Skinner Adams T, Trenholme K, Gardiner D, Whisstock J, et al. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS ONE. 2012;7:e31938 pubmed publisherPlasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, ..
- Hearn A, York I, Rock K. The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum. J Immunol. 2009;183:5526-36 pubmed publisherb>Aminopeptidases in the endoplasmic reticulum (ER) can cleave antigenic peptides and in so doing either create or destroy MHC class I-presented epitopes...
- Jia B, Lee S, Pham B, Kwack J, Jin H, Li J, et al. Biochemical characterization of deblocking aminopeptidases from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1. Biosci Biotechnol Biochem. 2011;75:1160-6 pubmed publisher..Finally, TkDAP1 was found to have higher deblocking aminopeptidase activity on the substrates of Ac-Leu-pNA and Ac-Ala-Ala-Ala, while TkDAP2 had higher aminopeptidase activity on the substrates of Leu-pNA and Ala-Ala-Ala-pNA...
- Andres A, Dennis M, Kretzschmar W, Cannons J, Lee Lin S, Hurle B, et al. Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet. 2010;6:e1001157 pubmed publisher..Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection. ..
- Zervoudi E, Papakyriakou A, Georgiadou D, Evnouchidou I, Gajda A, Poreba M, et al. Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides. Biochem J. 2011;435:411-20 pubmed publisher..These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the ..
- Cagliani R, Riva S, Biasin M, Fumagalli M, Pozzoli U, Lo Caputo S, et al. Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection. Hum Mol Genet. 2010;19:4705-14 pubmed publisherHuman ERAP1 and ERAP2 encode two endoplasmic reticulum aminopeptidases. These enzymes trim peptides to optimal size for loading onto major histocompatibility complex class I molecules and shape the antigenic repertoire presented to CD8(+)..
- Xiao Q, Zhang F, Nacev B, Liu J, Pei D. Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry. 2010;49:5588-99 pubmed publisher..In addition, the human MetAPs disfavor acidic residues at the P2'-P5' positions. The specificity data have allowed us to formulate a simple set of rules that can reliably predict the N-terminal processing of E. coli and human proteins. ..
- Drag M, Bogyo M, Ellman J, Salvesen G. Aminopeptidase fingerprints, an integrated approach for identification of good substrates and optimal inhibitors. J Biol Chem. 2010;285:3310-8 pubmed publisherb>Aminopeptidases process the N-terminal amino acids of target substrates by sequential cleavage of one residue at a time...
- Pazár B, Safrany E, Gergely P, Szanto S, Szekanecz Z, Poor G. Association of ARTS1 gene polymorphisms with ankylosing spondylitis in the Hungarian population: the rs27044 variant is associated with HLA-B*2705 subtype in Hungarian patients with ankylosing spondylitis. J Rheumatol. 2010;37:379-84 pubmed publisher..Our results suggest that the ARTS1 gene variants together with HLA-B27 strongly contribute to disease susceptibility in patients with AS. ..
- Olaleye O, Raghunand T, Bhat S, He J, Tyagi S, Lamichhane G, et al. Methionine aminopeptidases from Mycobacterium tuberculosis as novel antimycobacterial targets. Chem Biol. 2010;17:86-97 pubmed publisher..Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents. ..
- Trenholme K, Brown C, Skinner Adams T, Stack C, Lowther J, To J, et al. Aminopeptidases of malaria parasites: new targets for chemotherapy. Infect Disord Drug Targets. 2010;10:217-25 pubmed..falciparum, that may have the potential to become new targets for antimalarial drug development are the aminopeptidases. These enzymes catalyse the cleavage of the N-terminal amino acids from proteins and peptides. P...
- Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, et al. Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau. Psychogeriatrics. 2009;9:157-66 pubmed publisher..Together, the data suggest that attenuated proteolysis of FTDP-17 mutant tau may be explained by increased phosphorylation levels, resulting in resistance to proteolysis. ..
- Zhang Y, Chen L, Han X, Xie W, Kim H, Yang D, et al. Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc Natl Acad Sci U S A. 2013;110:5457-62 pubmed publisher..Our findings provide insight into the regulatory pathways and structural basis that control cell cycle-dependent telomerase recruitment and telomere elongation through phosphorylation of TPP1. ..
- Birtley J, Saridakis E, Stratikos E, Mavridis I. The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. Biochemistry. 2012;51:286-95 pubmed publisherEndoplasmic reticulum aminopeptidases ERAP1 and ERAP2 cooperate to trim a vast variety of antigenic peptide precursors to generate mature epitopes for binding to major histocompatibility class I molecules...
- Evnouchidou I, Papakyriakou A, Stratikos E. A new role for Zn(II) aminopeptidases: antigenic peptide generation and destruction. Curr Pharm Des. 2009;15:3656-70 pubmedDuring the last few years a novel role for previously known Zn(II) aminopeptidases has emerged, attracting a great deal of scientific interest to these molecules...
- Evans D, Spencer C, Pointon J, Su Z, Harvey D, Kochan G, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 2011;43:761-7 pubmed publisher..These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides. ..
- Goto Y, Ogawa K, Hattori A, Tsujimoto M. Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-gamma. J Biol Chem. 2011;286:21906-14 pubmed publisher..Our data reveal ERAP1-mediated activation of macrophages for the first time and will provide new insights into the role of this enzyme in innate immunity. ..
- McGowan S, Oellig C, Birru W, Caradoc Davies T, Stack C, Lowther J, et al. Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases. Proc Natl Acad Sci U S A. 2010;107:2449-54 pubmed publisher..The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth ..
- Lu J, Ye Q. Expression and characterization of Mycobacterium tuberculosis methionine aminopeptidase type 1a. Bioorg Med Chem Lett. 2010;20:2776-9 pubmed publisher..The differences in catalysis and inhibition predicted the significant differences in active site structure. ..
- Harbut M, Velmourougane G, Dalal S, Reiss G, Whisstock J, Onder O, et al. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. Proc Natl Acad Sci U S A. 2011;108:E526-34 pubmed publisher..falciparum metallo-aminopeptidases (MAPs), PfA-M1 and Pf-LAP...
- Bang S, Kim T, Lee B, Kwon E, Choi S, Lee K, et al. Genetic studies of ankylosing spondylitis in Koreans confirm associations with ERAP1 and 2p15 reported in white patients. J Rheumatol. 2011;38:322-4 pubmed publisher..This is the first confirmation in a nonwhite population that genetic polymorphisms of rs27037, rs27434, and rs10865331 are associated with AS, implicating common pathogenetic mechanisms in Korean and white patients with AS. ..
- Kim E, Kwak H, Ahn K. Cytosolic aminopeptidases influence MHC class I-mediated antigen presentation in an allele-dependent manner. J Immunol. 2009;183:7379-87 pubmed publisher..Several cytosolic aminopeptidases further trim proteasomal products to form mature epitopes or individual amino acids...
- Hosein F, Bandyopadhyay A, Peer W, Murphy A. The catalytic and protein-protein interaction domains are required for APM1 function. Plant Physiol. 2010;152:2158-72 pubmed publisher..These results suggest that both the catalytic and interaction domains are necessary for APM1 function but that APM1 function and dimerization do not require these domains to be present in the same linear molecule. ..
- Menzies F, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, et al. Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genet. 2010;19:4573-86 pubmed publisher..Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity. ..
- Schönegge A, Villa E, Förster F, Hegerl R, Peters J, Baumeister W, et al. The structure of human tripeptidyl peptidase II as determined by a hybrid approach. Structure. 2012;20:593-603 pubmed publisher..Analyses of the resulting hybrid structure of the HsTPPII holocomplex provide new insights into the mechanism of maturation and activation. ..
- Azimzadeh O, Sow C, G ze M, Nyalwidhe J, Florent I. Plasmodium falciparum PfA-M1 aminopeptidase is trafficked via the parasitophorous vacuole and marginally delivered to the food vacuole. Malar J. 2010;9:189 pubmed publisher..These results provide insights on PfA-M1 topology regarding key compartments of the infected red blood cells that have important implications for the development of inhibitors targeting this plasmodial enzyme...
- Samarasinghe B, Knox D, Britton C. Factors affecting susceptibility to RNA interference in Haemonchus contortus and in vivo silencing of an H11 aminopeptidase gene. Int J Parasitol. 2011;41:51-9 pubmed publisher..Thus, in this study we have established that RNAi is a valid and feasible approach to identify essential gene function. However, using current methods, this may be limited to genes expressed in accessible sites...
- Davidson S, Wu X, Liu Y, Wei M, Danoy P, Thomas G, et al. Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2009;60:3263-8 pubmed publisher..Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population...
- Yuga M, Gomi K, Klionsky D, Shintani T. Aspartyl aminopeptidase is imported from the cytoplasm to the vacuole by selective autophagy in Saccharomyces cerevisiae. J Biol Chem. 2011;286:13704-13 pubmed publisher..We propose that the cytosolic Ape4 is redistributed to the vacuole when yeast cells need more active vacuolar degradation. ..
- Hearn A, York I, Bishop C, Rock K. Characterizing the specificity and cooperation of aminopeptidases in the cytosol and endoplasmic reticulum during MHC class I antigen presentation. J Immunol. 2010;184:4725-32 pubmed publisher..These peptides can subsequently be trimmed by aminopeptidases in the cytosol and/or the endoplasmic reticulum (ER) to produce mature epitope...
- Kamphausen E, Kellert C, Abbas T, Akkad N, Tenzer S, Pawelec G, et al. Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma. Cancer Immunol Immunother. 2010;59:1273-84 pubmed publisher..The ER-resident aminopeptidases ERAP1 and ERAP2 trim or even destroy HLA class I-binding peptides thereby shaping the peptide repertoire ..
- Fierabracci A, Milillo A, Locatelli F, Fruci D. The putative role of endoplasmic reticulum aminopeptidases in autoimmunity: insights from genomic-wide association studies. Autoimmun Rev. 2012;12:281-8 pubmed publisher..In the endoplasmic reticulum (ER), aminopeptidases ERAP1 and ERAP2 display distinct trimming activity before antigenic peptides are loaded onto MHC class I ..
- Hill L, Hilliard D, York T, Srinivas S, Kusanovic J, Gomez R, et al. Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study. BMC Med Genet. 2011;12:64 pubmed publisher..This provides strong evidence that ERAP2 plays a role in the development of preeclampsia. ..
- O Toole J, Liu Y, Davis E, Westlake C, Attanasio M, Otto E, et al. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest. 2010;120:791-802 pubmed publisher..Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways. ..
- Haroon N, Tsui F, Chiu B, Tsui H, Inman R. Serum cytokine receptors in ankylosing spondylitis: relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms. J Rheumatol. 2010;37:1907-10 pubmed publisher..Soluble TNFRI levels correlate with ESR and CRP in AS. The ERAP1 and ERAP2 polymorphisms associated with AS do not influence the serum cytokine receptor levels in patients with AS. ..
- Kadi A, Izac B, Said Nahal R, Leboime A, Van Praet L, de Vlam K, et al. Investigating the genetic association between ERAP1 and spondyloarthritis. Ann Rheum Dis. 2013;72:608-13 pubmed publisher..This is the first study to show an association between several polymorphisms located in ERAP1 and SpA as a whole. Our findings demonstrate consistent association of the same SNPs and haplotypes with both AS and non-AS subtypes of SpA. ..
- Schechter I, Ziv E. Cathepsins S, B and L with aminopeptidases display ?-secretase activity associated with the pathogenesis of Alzheimer's disease. Biol Chem. 2011;392:555-69 pubmed publisher..The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp...
- Lowenberg B, Morgan G, Ossenkoppele G, Burnett A, Zachee P, Duhrsen U, et al. Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2010;28:4333-8 pubmed publisher..This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted. ..
- Nguyen T, Chang S, Evnouchidou I, York I, Zikos C, Rock K, et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nat Struct Mol Biol. 2011;18:604-13 pubmed publisher..ERAP1's unique structural elements suggest how a generic aminopeptidase structure has been adapted for the specialized function of trimming antigenic precursors. ..
- Evnouchidou I, Kamal R, Seregin S, Goto Y, Tsujimoto M, Hattori A, et al. Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J Immunol. 2011;186:1909-13 pubmed publisher..We propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity. ..
- Skinner Adams T, Stack C, Trenholme K, Brown C, Grembecka J, Lowther J, et al. Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials. Trends Biochem Sci. 2010;35:53-61 pubmed publisherThe neutral aminopeptidases M1 alanyl aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) of the human malaria parasite Plasmodium falciparum are targets for the development of novel anti-malarial drugs...
- Kim S, Lee S, Shin J, Kim Y, Evnouchidou I, Kim D, et al. Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol. 2011;12:984-91 pubmed publisher..Our findings identify a previously unknown viral miRNA-based CTL-evasion mechanism that targets a key step in the MHC class I antigen-processing pathway. ..
- Kumaki Y, Ogawa M, Hirano T, Yoshikawa K, Iwasawa N, Yagi T, et al. Family M42 aminopeptidase from the syntrophic bacterium Symbiobacterium thermophilum: characterization using recombinant protein. J Biosci Bioeng. 2011;111:134-9 pubmed publisher..thermophile Symbiobacterium thermophilum contains open reading frames of the genes encoding family M42 aminopeptidases, Pep1079, Pep1080, and Pep1081...
- Georgiadou D, Hearn A, Evnouchidou I, Chroni A, Leondiadis L, York I, et al. Placental leucine aminopeptidase efficiently generates mature antigenic peptides in vitro but in patterns distinct from endoplasmic reticulum aminopeptidase 1. J Immunol. 2010;185:1584-92 pubmed publisherAll three members of the oxytocinase subfamily of M1 aminopeptidases, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and placental leucine aminopeptidase (PLAP), also known as insulin-regulated aminopeptidase, have been ..
- Haroon N, Inman R. Endoplasmic reticulum aminopeptidases: Biology and pathogenic potential. Nat Rev Rheumatol. 2010;6:461-7 pubmed publisher..Furthermore, ERAP1 has been shown to be involved in shedding cytokine receptors. Both of these functions require further analysis to better understand the exact role of ERAP1 in AS. ..
- Pérez Abud R, Rodríguez Gómez I, Villarejo A, Moreno J, Wangensteen R, Tassi M, et al. Salt sensitivity in experimental thyroid disorders in rats. Am J Physiol Endocrinol Metab. 2011;301:E281-7 pubmed publisher..Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats...
- Forloni M, Albini S, Limongi M, Cifaldi L, Boldrini R, Nicotra M, et al. NF-kappaB, and not MYCN, regulates MHC class I and endoplasmic reticulum aminopeptidases in human neuroblastoma cells. Cancer Res. 2010;70:916-24 pubmed publisher..Moreover, we showed that the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, which generate MHC class I binding peptides, are regulated by NF-kappaB, contain functional ..
- Lu J, Yuan X, Yuan H, Wang W, Wan B, Franzblau S, et al. Inhibition of Mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives. ChemMedChem. 2011;6:1041-8 pubmed publisher..tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity. ..