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Title: Metap2  
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Subject: Proteases, Carboxypeptidase A6, Glutamate carboxypeptidase II, Carboxypeptidase B, Carboxypeptidase A
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Methionyl aminopeptidase 2

PDB rendering based on 1b59.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; MAP2; MNPEP; p67; p67eIF2
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.[1][2]

Methionine aminopeptidase 2, a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal methionine residues from nascent proteins.[3][4][5]

  • peptide-methionine \rightleftharpoons peptide + methionine

MetAP2 is found in all organisms and is especially important because of its critical role in tissue repair and protein degradation.[3] Furthermore, MetAP2 is of particular interest because the enzyme plays a key role in angiogenesis, the growth of new blood vessels, which is necessary for the progression of diseases including solid tumor cancers and rheumatoid arthritis.[6] MetAP2 is also the target of two groups of anti-angiogenic natural products, ovalicin and fumagillin, and their analogs.[7][8][9][10]


In living organisms, the start monomeric enzyme coded for by a gene consisting of 264 codons.[3] The knockout of this gene in E. coli leads to cell inviability.[11] In humans, there are two genes encoding MetAP, MetAP1 and MetAP2. MetAP1 codes for a 42 kDa enzyme, while MetAP2 codes for a 67 kDa enzyme. Yeast MetAP1 is 40 percent homologous to E. coli MetAP; within S. cerevisiae, MetAP2 is 22 percent homologous with the sequence of MetAP1; MetAP2 is highly conserved between S. cerevisiae and humans.[12] In contrast to prokaryotes, eukaryotic S. cerevisiae strains lacking the gene for either MetAP1 or MetAP2 are viable, but exhibit a slower growth rate than a control strain expressing both genes.

Figure 1. Active site structure of MetAP2. Generated using PDB:1BOA in PyMol. Click to view rotatable structure

Active site

The active site of MetAP2 has a structural motif characteristic of many metalloenzymes—including the dioxygen carrier protein, hemerythrin; the dinuclear non-heme iron protein, ribonucleotide reductase; leucine aminopeptidase; urease; arginase; several phosphatases and phosphoesterases—that includes two bridging carboxylate ligands and a bridging water or hydroxide ligand.[3][4][13][14][15][16][17] Specifically in human MetAP2 (PDB: 1BOA), one of the catalytic metal ions is bound to His331, Glu364, Glu459, Asp263, and a bridging water or hydroxide, while the other metal ion is bound to Asp251 (bidentate), App262 (bidentate), Glu459, and the same bridging water or hydroxide. Here, the two bridging carboxylates are Asp262 and Glu459.

Dimetal center

The identity of the active site metal ions under physiological conditions has not been successfully established, and remains a controversial issue. MetAP2 shows activity in the presence of Zn(II), Co(II), Mn(II), and Fe(II) ions, and various authors have argued any given metal ion is the physiological one: some in the presence of iron,[18] others in cobalt,[19][20] others in manganese,[21] and yet others in the presence of zinc.[22] Nonetheless, the majority of crystallographers have crystallized MetAP2 either in the presence of Zn(II) or Co(II) (see PDB database).


Figure 2. Two proposed reaction mechanisms for MetAP in E. coli. (A) Tetrahedral intermediate stabilized by Glu204 and metal center. (B) Tetrahedral intermediate stabilized His178 and metal center.[23]

The bridging water or hydroxide ligand acts as a nucleophile during the hydrolysis reaction, but the exact mechanism of catalysis is not yet known.[6][15][24] The catalytic mechanisms of hydrolase enzymes depend greatly on the identity of the bridging ligand,[25] which can be challenging to determine due to the difficulty of studying hydrogen atoms via x-ray crystallography.

The histidine residues shown in the mechanism to the right, H178 and H79, are conserved in all MetAPs (MetAP1s and MetAP2s) sequenced to date, suggesting their presence is important to catalytic activity.[26] Based upon X-ray crystallographic data, histidine 79 (H79) has been proposed to help position the methionine residue in the active site and transfer a proton to the newly exposed N-terminal amine.[8] Lowther and Colleagues have proposed two possible mechanisms for MetAP2 in E. coli, shown at the right.[10]


While previous studies have indicated MetAP2 catalyzes the removal of N-terminal methionine residues in vitro, the function of this enzyme in vivo may be more complex. For example, a significant correlation exists between the inhibition of the enzymatic activity of MetAP2 and inhibition of cell growth, thus implicating the enzyme in endothelial cell proliferation.[9] For this reason, scientists have singled out MetAP2 as a potential target for the inhibition of angiogenesis. Moreover, studies have demonstrated that MetAP2 copurifies and interacts with the α subunit of eukaryotic initiation factor 2 (eIF2), a protein that is necessary for protein synthesis in vivo.[27] Specifically, MetAP2 protects eIF-2α from inhibitory phosphorylation from the enzyme eIF-2α kinase, inhibits RNA-dependent protein kinase (PKR)-catalyzed eIF-2 R-subunit phosphorylation, and also reverses PKR-mediated inhibition of protein synthesis in intact cells.

Clinical significance

Figure 3. Fumagillin (green and red) bound to human MetAP2 active site (multicolored, with cyan, purple, and pink corresponding to helices, sheets, and loops, respectively), with dimetal ions (blue) shown.

Numerous studies implicate MetAP2 in angiogenesis.[9][16][28][29][30] Specifically, the [9] Thus far, both fumagillin and TNP-470 have been shown to possess antimalarial activity both in vitro and in vivo, and fumarranol, another fumagillin analog, represents a promising lead.[30]

Another METAP2 inhibitor beloranib (ZGN-433) has shown efficacy in reducing weight in severely obese subjects.[31] MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat, leading to substantial loss of body weight.


METAP2 has been shown to interact with Protein kinase R.[32]


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  2. ^ Li X, Chang YH (November 1996). "Evidence that the human homologue of a rat initiation factor-2 associated protein (p67) is a methionine aminopeptidase". Biochem Biophys Res Commun 227 (1): 152–9.  
  3. ^ a b c d e Bennett, B Holz, RC (1997). "EPR Studies on the Mono- and Dicobalt(II)-Substituted Forms of the Aminopeptidase from Aeromonas proteolytica. Insight into the Catalytic Mechanism of Dinuclear Hydrolases". J. Am. Chem. Soc. 119: 1923–1933.  
  4. ^ a b Johansson FB, Bond AD, Nielsen UG, Moubaraki B, Murray KS, Berry KJ, Larrabee JA, McKenzie CJ (June 2008). "Dicobalt II-II, II-III, and III-III complexes as spectroscopic models for dicobalt enzyme active sites". Inorg Chem 47 (12): 5079–92.  
  5. ^ Larrabee JA, Leung CH, Moore RL, Thamrong-nawasawat T, Wessler BS (October 2004). "Magnetic circular dichroism and cobalt(II) binding equilibrium studies of Escherichia coli methionyl aminopeptidase". J. Am. Chem. Soc. 126 (39): 12316–24.  
  6. ^ a b Folkman J (January 1995). "Angiogenesis in cancer, vascular, rheumatoid and other disease". Nat. Med. 1 (1): 27–31.  
  7. ^ Taunton J (July 1997). "How to starve a tumor". Chem. Biol. 4 (7): 493–6.  
  8. ^ a b Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM (June 1997). "The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2". Proc. Natl. Acad. Sci. U.S.A. 94 (12): 6099–103.  
  9. ^ a b c d Griffith EC, Su Z, Turk BE, Chen S, Chang YH, Wu Z, Biemann K, Liu JO (June 1997). "Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin". Chem. Biol. 4 (6): 461–71.  
  10. ^ a b Lowther WT, McMillen DA, Orville AM, Matthews BW (October 1998). "The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12153–7.  
  11. ^ Chang SY, McGary EC, Chang S (July 1989). "Methionine aminopeptidase gene of Escherichia coli is essential for cell growth". J. Bacteriol. 171 (7): 4071–2.  
  12. ^ Li X, Chang YH (December 1995). "Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases". Proc. Natl. Acad. Sci. U.S.A. 92 (26): 12357–61.  
  13. ^ Mizoguchi TJ, Kuzelka J, Spingler B, DuBois JL, Davydov RM, Hedman B, Hodgson KO, Lippard SJ (August 2001). "Synthesis and spectroscopic studies of non-heme diiron(III) species with a terminal hydroperoxide ligand: models for hemerythrin". Inorg Chem 40 (18): 4662–73.  
  14. ^ Hagen KS, Lachicotte R, Kitaygorodskiy A (1993). "Supramolecular Control of Stepwise and Selective Carboxylate Ligand Substitution in Aqua-Carboxylato-Bridged Dimetal(II) Complexes". J. Am. Chem. Soc. 115: 12617–12618.  
  15. ^ a b Brown DA, Errington W, Glass WK, Haase W, Kemp TJ, Nimir H, Ostrovsky SM, Werner R (November 2001). "Magnetic, spectroscopic, and structural studies of dicobalt hydroxamates and model hydrolases". Inorg Chem 40 (23): 5962–71.  
  16. ^ a b Larrabee JA, Chyun SA, Volwiler AS (November 2008). "Magnetic circular dichroism study of a dicobalt(II) methionine aminopeptidase/fumagillin complex and dicobalt II-II and II-III model complexes". Inorg Chem 47 (22): 10499–508.  
  17. ^ Wilcox DE (November 1996). "Binuclear Metallohydrolases". Chem. Rev. 96 (7): 2435–2458.  
  18. ^ D'souza VM, Holz RC (August 1999). "The methionyl aminopeptidase from Escherichia coli can function as an iron(II) enzyme". Biochemistry 38 (34): 11079–85.  
  19. ^ Chang YH, Teichert U, Smith JA (April 1992). "Molecular cloning, sequencing, deletion, and overexpression of a methionine aminopeptidase gene from Saccharomyces cerevisiae". J. Biol. Chem. 267 (12): 8007–11.  
  20. ^ Ghosh M, Grunden AM, Dunn DM, Weiss R, Adams MW (September 1998). "Characterization of native and recombinant forms of an unusual cobalt-dependent proline dipeptidase (prolidase) from the hyperthermophilic archaeon Pyrococcus furiosus". J. Bacteriol. 180 (18): 4781–9.  
  21. ^ Wang J, Sheppard GS, Lou P, Kawai M, Park C, Egan DA, Schneider A, Bouska J, Lesniewski R, Henkin J (May 2003). "Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese". Biochemistry 42 (17): 5035–42.  
  22. ^ Leopoldini M, Russo N, Toscano M (June 2007). "Which one among Zn(II), Co(II), Mn(II), and Fe(II) is the most efficient ion for the methionine aminopeptidase catalyzed reaction?". J. Am. Chem. Soc. 129 (25): 7776–84.  
  23. ^ Lowther WT, Zhang Y, Sampson PB, Honek JF, Matthews BW (November 1999). "Insights into the mechanism of Escherichia coli methionine aminopeptidase from the structural analysis of reaction products and phosphorus-based transition-state analogues". Biochemistry 38 (45): 14810–9.  
  24. ^ Schultz BE, Ye B, Li X, Chan SI (1997). "Electronic Paramagnetic Resonance and Magnetic Properties of Model Complexes for Binuclear Active Sites in Hydrolase Enzymes". Inorg. Chem. 36: 2617–2622.  
  25. ^ Korendovych IV, Kryatov SV, Reiff WM, Rybak-Akimova EV (November 2005). "Diiron(II) mu-aqua-mu-hydroxo model for non-heme iron sites in proteins". Inorg Chem 44 (24): 8656–8.  
  26. ^ Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ, Ye QZ (May 2004). "Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity". J. Biol. Chem. 279 (20): 21128–34.  
  27. ^ Wu S, Rehemtulla A, Gupta NK, Kaufman RJ (June 1996). "A eukaryotic translation initiation factor 2-associated 67 kDa glycoprotein partially reverses protein synthesis inhibition by activated double-stranded RNA-dependent protein kinase in intact cells". Biochemistry 35 (25): 8275–80.  
  28. ^ Benny O, Fainaru O, Adini A, Cassiola F, Bazinet L, Adini I, Pravda E, Nahmias Y, Koirala S, Corfas G, D'Amato RJ, Folkman J (July 2008). "An orally delivered small-molecule formulation with antiangiogenic and anticancer activity". Nat. Biotechnol. 26 (7): 799–807.  
  29. ^ a b Sato Y (2004). "Aminopeptidases in Health and Disease: Role of Aminopeptidase in Angiogenesis". Biol. Pharm. Bull. 27: 772–776.  
  30. ^ a b c Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO (February 2009). "Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo". Chem. Biol. 16 (2): 193–202.  
  31. ^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. 2011-01-01. Retrieved 2011-04-13. 
  32. ^ Gil J, Esteban M, Roth D (December 2000). "In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67". Biochemistry 39 (51): 16016–25.  

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