Methionine aminopeptidase 2

NameMethionine aminopeptidase 2
Synonyms
  • 3.4.11.18
  • Initiation factor 2-associated 67 kDa glycoprotein
  • MAP 2
  • MNPEP
  • p67
  • P67EIF2
  • Peptidase M
Gene NameMETAP2
OrganismHuman
Amino acid sequence
>lcl|BSEQ0003046|Methionine aminopeptidase 2
MAGVEEVAASGSHLNGDLDPDDREEGAASTAEEAAKKKRRKKKKSKGPSAAGEQEPDKES
GASVDEVARQLERSALEDKERDEDDEDGDGDGDGATGKKKKKKKKKRGPKVQTDPPSVPI
CDLYPNGVFPKGQECEYPPTQDGRTAAWRTTSEEKKALDQASEEIWNDFREAAEAHRQVR
KYVMSWIKPGMTMIEICEKLEDCSRKLIKENGLNAGLAFPTGCSLNNCAAHYTPNAGDTT
VLQYDDICKIDFGTHISGRIIDCAFTVTFNPKYDTLLKAVKDATNTGIKCAGIDVRLCDV
GEAIQEVMESYEVEIDGKTYQVKPIRNLNGHSIGQYRIHAGKTVPIVKGGEATRMEEGEV
YAIETFGSTGKGVVHDDMECSHYMKNFDVGHVPIRLPRTKHLLNVINENFGTLAFCRRWL
DRLGESKYLMALKNLCDLGIVDPYPPLCDIKGSYTAQFEHTILLRPTCKEVVSRGDDY
Number of residues478
Molecular Weight52891.145
Theoretical pI5.57
GO Classification
Functions
  • metalloexopeptidase activity
  • metal ion binding
  • aminopeptidase activity
  • poly(A) RNA binding
  • metalloaminopeptidase activity
Processes
  • protein processing
  • phototransduction, visible light
  • protein initiator methionine removal
  • N-terminal protein amino acid modification
  • peptidyl-methionine modification
  • regulation of rhodopsin mediated signaling pathway
  • rhodopsin mediated signaling pathway
Components
  • cytosol
  • cytoplasm
  • plasma membrane
General FunctionPoly(a) rna binding
Specific FunctionCotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo.Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID903982
UniProtKB IDP50579
UniProtKB Entry NameMAP2_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0020537|Methionine aminopeptidase 2 (METAP2)
ATGGCGGGTGTGGAGGAGGTAGCGGCCTCCGGGAGCCACCTGAATGGCGACCTGGATCCA
GACGACAGGGAAGAAGGAGCTGCCTCTACGGCTGAGGAAGCAGCCAAGAAAAAAAGACGA
AAGAAGAAGAAGAGCAAAGGGCCTTCTGCAGCAGGGGAACAGGAACCTGATAAAGAATCA
GGAGCCTCAGTGGATGAAGTAGCAAGACAGTTGGAAAGATCAGCATTGGAAGATAAAGAA
AGAGATGAAGATGATGAAGATGGAGATGGCGATGGAGATGGAGCAACTGGAAAGAAGAAG
AAAAAGAAGAAGAAGAAGAGAGGACCAAAAGTTCAAACAGACCCTCCCTCAGTTCCAATA
TGTGACCTGTATCCTAATGGTGTATTTCCCAAAGGACAAGAATGCGAATACCCACCCACA
CAAGATGGGCGAACAGCTGCTTGGAGAACTACAAGTGAAGAAAAGAAAGCATTAGATCAG
GCAAGTGAAGAGATTTGGAATGATTTTCGAGAAGCTGCAGAAGCACATCGACAAGTTAGA
AAATACGTAATGAGCTGGATCAAGCCTGGGATGACAATGATAGAAATCTGTGAAAAGTTG
GAAGACTGTTCACGCAAGTTAATAAAAGAGAATGGATTAAATGCAGGCCTGGCATTTCCT
ACTGGATGTTCTCTCAATAATTGTGCTGCCCATTATACTCCCAATGCCGGTGACACAACA
GTATTACAGTATGATGACATCTGTAAAATAGACTTTGGAACACATATAAGTGGTAGGATT
ATTGACTGTGCTTTTACTGTCACTTTTAATCCCAAATATGATACGTTATTAAAAGCTGTA
AAAGATGCTACTAACACTGGAATAAAGTGTGCTGGAATTGATGTTCGTCTGTGTGATGTT
GGTGAGGCCATCCAAGAAGTTATGGAGTCCTATGAAGTTGAAATAGATGGGAAGACATAT
CAAGTGAAACCAATCCGTAATCTAAATGGACATTCAATTGGGCAATATAGAATACATGCT
GGAAAAACAGTGCCGATTGTGAAAGGAGGGGAGGCAACAAGAATGGAGGAAGGAGAAGTA
TATGCAATTGAAACCTTTGGTAGTACAGGAAAAGGTGTTGTTCATGATGATATGGAATGT
TCACATTACATGAAAAATTTTGATGTTGGACATGTGCCAATAAGGCTTCCAAGAACAAAA
CACTTGTTAAATGTCATCAATGAAAACTTTGGAACCCTTGCCTTCTGCCGCAGATGGCTG
GATCGCTTGGGAGAAAGTAAATACTTGATGGCTCTGAAGAATCTGTGTGACTTGGGCATT
GTAGATCCATATCCACCATTATGTGACATTAAAGGATCATATACAGCGCAATTTGAACAT
ACCATCCTGTTGCGTCCAACATGTAAAGAAGTTGTCAGCAGAGGAGATGACTATTAA
GenBank Gene IDU29607
GeneCard IDNot Available
GenAtlas IDMETAP2
HGNC IDHGNC:16672
Chromosome Location12
Locus12q22
References
  1. Arfin SM, Kendall RL, Hall L, Weaver LH, Stewart AE, Matthews BW, Bradshaw RA: Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent enzymes. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7714-8. 7644482
  2. Li X, Chang YH: Molecular cloning of a human complementary DNA encoding an initiation factor 2-associated protein (p67). Biochim Biophys Acta. 1995 Feb 21;1260(3):333-6. 7873610
  3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  4. Scherer SE, Muzny DM, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Montgomery KT, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Lovering RC, Wheeler DA, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clerc-Blankenburg KP, Davis C, Delgado O, Dinh HH, Draper H, Gonzalez-Garay ML, Havlak P, Jackson LR, Jacob LS, Kelly SH, Li L, Li Z, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Pasternak S, Perez LM, Plopper FJ, Santibanez J, Shen H, Tabor PE, Verduzco D, Waldron L, Wang Q, Williams GA, Zhang J, Zhou J, Allen CC, Amin AG, Anyalebechi V, Bailey M, Barbaria JA, Bimage KE, Bryant NP, Burch PE, Burkett CE, Burrell KL, Calderon E, Cardenas V, Carter K, Casias K, Cavazos I, Cavazos SR, Ceasar H, Chacko J, Chan SN, Chavez D, Christopoulos C, Chu J, Cockrell R, Cox CD, Dang M, Dathorne SR, David R, Davis CM, Davy-Carroll L, Deshazo DR, Donlin JE, D'Souza L, Eaves KA, Egan A, Emery-Cohen AJ, Escotto M, Flagg N, Forbes LD, Gabisi AM, Garza M, Hamilton C, Henderson N, Hernandez O, Hines S, Hogues ME, Huang M, Idlebird DG, Johnson R, Jolivet A, Jones S, Kagan R, King LM, Leal B, Lebow H, Lee S, LeVan JM, Lewis LC, London P, Lorensuhewa LM, Loulseged H, Lovett DA, Lucier A, Lucier RL, Ma J, Madu RC, Mapua P, Martindale AD, Martinez E, Massey E, Mawhiney S, Meador MG, Mendez S, Mercado C, Mercado IC, Merritt CE, Miner ZL, Minja E, Mitchell T, Mohabbat F, Mohabbat K, Montgomery B, Moore N, Morris S, Munidasa M, Ngo RN, Nguyen NB, Nickerson E, Nwaokelemeh OO, Nwokenkwo S, Obregon M, Oguh M, Oragunye N, Oviedo RJ, Parish BJ, Parker DN, Parrish J, Parks KL, Paul HA, Payton BA, Perez A, Perrin W, Pickens A, Primus EL, Pu LL, Puazo M, Quiles MM, Quiroz JB, Rabata D, Reeves K, Ruiz SJ, Shao H, Sisson I, Sonaike T, Sorelle RP, Sutton AE, Svatek AF, Svetz LA, Tamerisa KS, Taylor TR, Teague B, Thomas N, Thorn RD, Trejos ZY, Trevino BK, Ukegbu ON, Urban JB, Vasquez LI, Vera VA, Villasana DM, Wang L, Ward-Moore S, Warren JT, Wei X, White F, Williamson AL, Wleczyk R, Wooden HS, Wooden SH, Yen J, Yoon L, Yoon V, Zorrilla SE, Nelson D, Kucherlapati R, Weinstock G, Gibbs RA: The finished DNA sequence of human chromosome 12. Nature. 2006 Mar 16;440(7082):346-51. 16541075
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  6. Datta B, Ray MK, Chakrabarti D, Wylie DE, Gupta NK: Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) and its possible role in the inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2 alpha-subunit. J Biol Chem. 1989 Dec 5;264(34):20620-4. 2511207
  7. Wang J, Sheppard GS, Lou P, Kawai M, Park C, Egan DA, Schneider A, Bouska J, Lesniewski R, Henkin J: Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese. Biochemistry. 2003 May 6;42(17):5035-42. 12718546
  8. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. 18669648
  9. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. doi: 10.1021/ac9004309. 19413330
  10. Xiao Q, Zhang F, Nacev BA, Liu JO, Pei D: Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry. 2010 Jul 6;49(26):5588-99. doi: 10.1021/bi1005464. 20521764
  11. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. 20068231
  12. Wu S: Localization and function of a eukaryotic-initiation-factor-2-associated 67-kDa glycoprotein. World J Biol Chem. 2010 Oct 26;1(10):313-20. doi: 10.4331/wjbc.v1.i10.313. 21537465
  13. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  14. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  15. Liu S, Widom J, Kemp CW, Crews CM, Clardy J: Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science. 1998 Nov 13;282(5392):1324-7. 9812898
  16. Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE: Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J Biol Chem. 2003 Dec 26;278(52):52964-71. Epub 2003 Oct 8. 14534293
  17. Sheppard GS, Wang J, Kawai M, BaMaung NY, Craig RA, Erickson SA, Lynch L, Patel J, Yang F, Searle XB, Lou P, Park C, Kim KH, Henkin J, Lesniewski R: 3-Amino-2-hydroxyamides and related compounds as inhibitors of methionine aminopeptidase-2. Bioorg Med Chem Lett. 2004 Feb 23;14(4):865-8. 15012983
  18. Kallander LS, Lu Q, Chen W, Tomaszek T, Yang G, Tew D, Meek TD, Hofmann GA, Schulz-Pritchard CK, Smith WW, Janson CA, Ryan MD, Zhang GF, Johanson KO, Kirkpatrick RB, Ho TF, Fisher PW, Mattern MR, Johnson RK, Hansbury MJ, Winkler JD, Ward KW, Veber DF, Thompson SK: 4-Aryl-1,2,3-triazole: a novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. J Med Chem. 2005 Sep 8;48(18):5644-7. 16134930
  19. Nonato MC, Widom J, Clardy J: Human methionine aminopeptidase type 2 in complex with L- and D-methionine. Bioorg Med Chem Lett. 2006 May 15;16(10):2580-3. Epub 2006 Mar 15. 16540317
  20. Wang GT, Mantei RA, Kawai M, Tedrow JS, Barnes DM, Wang J, Zhang Q, Lou P, Garcia LA, Bouska J, Yates M, Park C, Judge RA, Lesniewski R, Sheppard GS, Bell RL: Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids. Bioorg Med Chem Lett. 2007 May 15;17(10):2817-22. Epub 2007 Feb 25. 17350258
  21. Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK: Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. 17636946