Izvorni kôd stranice MMTAP2

{{Infokutija gen}}
'''Metionin-aminopeptidaza 2''' jest [[enzim]] koji je kod [[ljudi]] [[kodon|kodiran]] [[gen]]om '''METAP2''' sa [[hromosom 16|hromosoma 6]].<ref name="pmid7644482">{{cite journal |vauthors=Arfin SM, Kendall RL, Hall L, Weaver LH, Stewart AE, Matthews BW, Bradshaw RA | title = Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent enzymes | journal = Proc Natl Acad Sci U S A | volume = 92 | issue = 17 | pages = 7714–8 | date=septembar 1995| pmid = 7644482 | pmc = 41216 | doi =10.1073/pnas.92.17.7714  | bibcode = 1995PNAS...92.7714A | doi-access = free }}</ref><ref name="pmid8858118">{{cite journal |vauthors=Li X, Chang YH | title = Evidence that the human homologue of a rat initiation factor-2 associated protein (p67) is a methionine aminopeptidase | journal = Biochem Biophys Res Commun | volume = 227 | issue = 1 | pages = 152–9 | date=novembar 1996| pmid = 8858118 | doi = 10.1006/bbrc.1996.1482 }}</ref>

==Aminokiselinska sekvenca==	
Dužina [[polipeptid]]nog lanca je  478 [[aminokiselina]], a [[molekularna masa|molekulska težina]]  52.892 [[dalton (jedinica)|Da]].<ref name="UniProt">{{cite web|url=http://www.uniprot.org/uniprot/P50579#sequences |title=UniProt, P50579 |language=en |access-date=12. 4. 2022}}</ref>
{{legenda aminokiselina}} 
<table  style="font-family:monospace;">
<tr style="text-align:right;"><th>10</th><th></th><th>20</th><th></th><th>30</th><th></th><th>40</th><th></th><th>50</th></tr>
<tr style="background-color: #eee;"><td>MAGVEEVAAS</td><td style="background-color: #f9f9f9;"></td><td>GSHLNGDLDP</td><td style="background-color: #f9f9f9;"></td><td>DDREEGAAST</td><td style="background-color: #f9f9f9;"></td><td>AEEAAKKKRR</td><td style="background-color: #f9f9f9;"></td><td>KKKKSKGPSA</td></tr>
<tr style="background-color: #eee;"><td>AGEQEPDKES</td><td style="background-color: #f9f9f9;"></td><td>GASVDEVARQ</td><td style="background-color: #f9f9f9;"></td><td>LERSALEDKE</td><td style="background-color: #f9f9f9;"></td><td>RDEDDEDGDG</td><td style="background-color: #f9f9f9;"></td><td>DGDGATGKKK</td></tr>
<tr style="background-color: #eee;"><td>KKKKKKRGPK</td><td style="background-color: #f9f9f9;"></td><td>VQTDPPSVPI</td><td style="background-color: #f9f9f9;"></td><td>CDLYPNGVFP</td><td style="background-color: #f9f9f9;"></td><td>KGQECEYPPT</td><td style="background-color: #f9f9f9;"></td><td>QDGRTAAWRT</td></tr>
<tr style="background-color: #eee;"><td>TSEEKKALDQ</td><td style="background-color: #f9f9f9;"></td><td>ASEEIWNDFR</td><td style="background-color: #f9f9f9;"></td><td>EAAEAHRQVR</td><td style="background-color: #f9f9f9;"></td><td>KYVMSWIKPG</td><td style="background-color: #f9f9f9;"></td><td>MTMIEICEKL</td></tr>
<tr style="background-color: #eee;"><td>EDCSRKLIKE</td><td style="background-color: #f9f9f9;"></td><td>NGLNAGLAFP</td><td style="background-color: #f9f9f9;"></td><td>TGCSLNNCAA</td><td style="background-color: #f9f9f9;"></td><td>HYTPNAGDTT</td><td style="background-color: #f9f9f9;"></td><td>VLQYDDICKI</td></tr>
<tr style="background-color: #eee;"><td>DFGTHISGRI</td><td style="background-color: #f9f9f9;"></td><td>IDCAFTVTFN</td><td style="background-color: #f9f9f9;"></td><td>PKYDTLLKAV</td><td style="background-color: #f9f9f9;"></td><td>KDATNTGIKC</td><td style="background-color: #f9f9f9;"></td><td>AGIDVRLCDV</td></tr>
<tr style="background-color: #eee;"><td>GEAIQEVMES</td><td style="background-color: #f9f9f9;"></td><td>YEVEIDGKTY</td><td style="background-color: #f9f9f9;"></td><td>QVKPIRNLNG</td><td style="background-color: #f9f9f9;"></td><td>HSIGQYRIHA</td><td style="background-color: #f9f9f9;"></td><td>GKTVPIVKGG</td></tr>
<tr style="background-color: #eee;"><td>EATRMEEGEV</td><td style="background-color: #f9f9f9;"></td><td>YAIETFGSTG</td><td style="background-color: #f9f9f9;"></td><td>KGVVHDDMEC</td><td style="background-color: #f9f9f9;"></td><td>SHYMKNFDVG</td><td style="background-color: #f9f9f9;"></td><td>HVPIRLPRTK</td></tr>
<tr style="background-color: #eee;"><td>HLLNVINENF</td><td style="background-color: #f9f9f9;"></td><td>GTLAFCRRWL</td><td style="background-color: #f9f9f9;"></td><td>DRLGESKYLM</td><td style="background-color: #f9f9f9;"></td><td>ALKNLCDLGI</td><td style="background-color: #f9f9f9;"></td><td>VDPYPPLCDI</td></tr>
<tr style="background-color: #eee;"><td>KGSYTAQFEH</td><td style="background-color: #f9f9f9;"></td><td>TILLRPTCKE</td><td style="background-color: #f9f9f9;"></td><td>VVSRGDDY</td></tr>
</table>

== Struktura ==

U živim organizmima, [[startni kodon]] koji pokreće [[Biosinteza proteina|sintezu proteina]] kodira ili metionin ([[eukarioti]]) ili [[formilmetionin]] ([[prokarioti]]). U ''[[E. coli]]'' (prokariot), [[enzim]] zvani [[formilmetionin-deformilaza]] može otcijepiti formilnu grupu, ostavljajući samo [[N-terminal]]ni ostatak metionina. Za proteine s malim, nenabijenim pretposljednjim N-terminalnim ostacima, metionin-aminopeptidaza može razdvojiti ostatak metionina.<ref name="isbnunkn1"/>
Broj [[gen]]a koji kodiraju metionin-aminopeptidazu varira između organizama. Kod ''[[E. coli]]'' postoji samo jedan poznati MetAP, za [[monomer]]ni enzim od 29,333 Da, kodiran genom koji se sastoji od 264 [[kodon]]a.<ref name= isbnunkn1/> [[genski nokaut|Nokaut ovog gena]] u ''E. coli'' dovodi do nesposobnosti ćelije.<ref name=isbnunkn19>{{cite journal |vauthors=Chang SY, McGary EC, Chang S | title = Methionine aminopeptidase gene of Escherichia coli is essential for cell growth | journal = J. Bacteriol. | volume = 171 | issue = 7 | pages = 4071–2 |date=juli 1989 | pmid = 2544569 | pmc = 210164 | doi = 10.1128/jb.171.7.4071-4072.1989}}</ref> Kod ljudi postoje dva gena koji kodiraju MetAP, [[MetAP1]] i MetAP2. MetAP1 kodira enzim od 42 kDa, dok MetAP2 kodira enzim od 67 kDa. [[Kvasac|Kvaščev]] MetAP1 je 40% homologan sa MetAP ''E. coli''; unutar ''[[S. cerevisiae]]'', MetAP2 je 22% [[Homologija sekvence|homologan]] sa sekvencom MetAP1; MetAP2 je visoko konzerviran između ''S. cerevisiae'' i ljudi.<ref name=isbnunkn20>{{cite journal |vauthors=Li X, Chang YH | title = Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 26 | pages = 12357–61 |date=decembar 1995 | pmid = 8618900 | pmc = 40356 | doi = 10.1073/pnas.92.26.12357| bibcode = 1995PNAS...9212357L | doi-access = free }}</ref> Za razliku od prokariota, eukariotski sojevi ''S. cerevisiae'' kojima nedostaje gen za MetAP1 ili MetAP2 su održivi, ali pokazuju sporiji rast od kontrolnog soja koji eksprimira oba gena.
[[slika:MetAP2 active site.ogv|thumb|upright=2.4|left|Slika 1: Struktura aktivne stranice MetAP2. Generirano korištenjem PDB:1BOA u PyMol. Kliknite da vidite rotirajuću strukturu]]

=== Aktivno mjesto ===

[[Aktivno mjesto]] MetAP2 ima strukturni motiv karakterističan za mnoge metaloenzime—uključujući protein nosač dikisika, [[hemeritrin]]; dijedarni ne-[[hem]] [[gvožđe]]ve proteine, [[ribonukleotid-reduktaza]], [[leucin-aminopeptidaza]], [[ureaza]],  [[arginaza]], nekoliko [[fosfataza]] i [[fosfoesteraza]]—što uključuje dva premošćavajuća [[karboksilat]] [[ligand]]a i premošćavajuću [[voda|vodu]] ili [[hidroksid]]ni [[ligand]].<ref name=isbnunkn1/><ref name=isbnunkn2 /><ref name=isbnunkn10>{{cite journal |vauthors=Mizoguchi TJ, Kuzelka J, Spingler B, DuBois JL, Davydov RM, Hedman B, Hodgson KO, Lippard SJ | title = Synthesis and spectroscopic studies of non-heme diiron(III) species with a terminal hydroperoxide ligand: models for hemerythrin | journal = Inorg Chem | volume = 40 | issue = 18 | pages = 4662–73 |date=august 2001 | pmid = 11511213 | doi = 10.1021/ic010076b }}</ref><ref name=isbnunkn11>{{cite journal |vauthors=Hagen KS, Lachicotte R, Kitaygorodskiy A | title = Supramolecular Control of Stepwise and Selective Carboxylate Ligand Substitution in Aqua-Carboxylato-Bridged Dimetal(II) Complexes | journal = J. Am. Chem. Soc. | volume = 115 | issue = 26 | pages = 12617–12618 | year =1993 | doi = 10.1021/ja00079a064 }}</ref><ref name=isbnunkn12>{{cite journal |vauthors=Brown DA, Errington W, Glass WK, Haase W, Kemp TJ, Nimir H, Ostrovsky SM, Werner R | title = Magnetic, spectroscopic, and structural studies of dicobalt hydroxamates and model hydrolases | journal = Inorg Chem | volume = 40 | issue = 23 | pages = 5962–71 |date=novembar 2001 | pmid = 11681912 | doi = 10.1021/ic0103345 }}</ref><ref name=isbnunkn13>{{cite journal |vauthors=Larrabee JA, Chyun SA, Volwiler AS | title = Magnetic circular dichroism study of a dicobalt(II) methionine aminopeptidase/fumagillin complex and dicobalt II-II and II-III model complexes | journal = Inorg Chem | volume = 47 | issue = 22 | pages = 10499–508 |date=novembar 2008 | pmid = 18921993 | doi = 10.1021/ic8011553 }}</ref><ref name=isbnunkn14>{{cite journal | author = Wilcox DE | title = Binuclear Metallohydrolases | journal = Chem. Rev. | volume = 96 | issue = 7 | pages = 2435–2458 |date=novembar 1996 | pmid = 11848832 | doi = 10.1021/cr950043b }}</ref> Konkretno, u ljudskom MetAP2 (PDB: 1BOA), jedan od katalitskih metalnih iona vezan je za His331, Glu364, Glu459, Asp263 i premošćavajuću vodu ili hidroksid, dok je drugi metalni ion vezan za Asp251 ([[bidentat]]) , App262 (bidentat), Glu459, istu premošivačku vodu ili hidroksid. Ovdje su dva premošćavajuća karboksilata Asp262 i Glu459.

=== Dimetalni centar ===

Identitet [[aktivno mjesto|aktivnog mjesta]] [[metal]]nog [[ion]]a u fiziološkim uvjetima nije uspješno utvrđen i ostaje kontroverzno pitanje. MetAP2 pokazuje aktivnost u prisustvu iona [[cink|Zn(II)]], [[kobalt|Co(II)]], [[mangan|Mn(II)]] i [[gvožđe|Fe(II)]], a različiti autori tvrde da je bilo koji metalni ion fiziološki: neki u prisustvu [[gvožđe|gvožđa]],<ref name="Dsouza">{{cite journal |vauthors=D'souza VM, Holz RC |date=august 1999 |title=The methionyl aminopeptidase from Escherichia coli can function as an iron(II) enzyme |url=https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1303&context=chem_fac |journal=Biochemistry |volume=38 |issue=34 |pages=11079–85 |doi=10.1021/bi990872h |pmid=10460163}}</ref> ostali  [[kobalt]]a,<ref name=isbnunkn23>{{cite journal |vauthors=Chang YH, Teichert U, Smith JA | title = Molecular cloning, sequencing, deletion, and overexpression of a methionine aminopeptidase gene from Saccharomyces cerevisiae | journal = J. Biol. Chem. | volume = 267 | issue = 12 | pages = 8007–11 |date=april 1992 | doi = 10.1016/S0021-9258(18)42400-3 | pmid = 1569059 | doi-access = free }}</ref><ref name=isbnunkn24>{{cite journal |vauthors=Ghosh M, Grunden AM, Dunn DM, Weiss R, Adams MW | title = Characterization of native and recombinant forms of an unusual cobalt-dependent proline dipeptidase (prolidase) from the hyperthermophilic archaeon Pyrococcus furiosus | journal = J. Bacteriol. | volume = 180 | issue = 18 | pages = 4781–9 |date=septembar 1998 | pmid = 9733678 | pmc = 107500 | doi = 10.1128/JB.180.18.4781-4789.1998}}</ref> ili [[magnezij]]a,<ref name=isbnunkn25>{{cite journal |vauthors=Wang J, Sheppard GS, Lou P, Kawai M, Park C, Egan DA, Schneider A, Bouska J, Lesniewski R, Henkin J | title = Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese | journal = Biochemistry | volume = 42 | issue = 17 | pages = 5035–42 |date=maj 2003 | pmid = 12718546 | doi = 10.1021/bi020670c }}</ref> a drugi u prisustvu [[cink]]a.<ref name=isbnunkn26>{{cite journal |vauthors=Leopoldini M, Russo N, Toscano M | title = Which one among Zn(II), Co(II), Mn(II), and Fe(II) is the most efficient ion for the methionine aminopeptidase catalyzed reaction? | journal = J. Am. Chem. Soc. | volume = 129 | issue = 25 | pages = 7776–84 |date=juni 2007 | pmid = 17523636 | doi = 10.1021/ja068168t }}</ref> Ipak, većina kristalografa ima [[kristalizacija|kristalizovan]] MetAP2 ili u prisustvu Zn(II) ili Co(II) (vidi [[PDB]] bazu podataka).

==Mehanizam==
[[slika:Mechanism of MetAP2.jpg|thumb|upright=3|right|Slika 2: Dva predložena mehanizma reakcije za MetAP u ''E. coli''. (A) Tetraedarski intermedijer stabiliziran Glu204 i metalnim centrom. (B) Tetraedarski intermedijer je stabilizovao His178 i metalni centar.<ref name=lowther40>{{cite journal |vauthors=Lowther WT, Zhang Y, Sampson PB, Honek JF, Matthews BW | title = Insights into the mechanism of Escherichia coli methionine aminopeptidase from the structural analysis of reaction products and phosphorus-based transition-state analogues | journal = Biochemistry | volume = 38 | issue = 45 | pages = 14810–9 |date=novembar 1999 | pmid = 10555963 | doi = 10.1021/bi991711g }}</ref>]]

Premosni vodeni ili hidroksidni [[ligand]] djeluje kao [[nukleofil]] tokom reakcije hidrolize, ali tačan mehanizam katalize još nije poznat.<ref name=isbnunkn12 /><ref name=isbnunkn4 /><ref name=isbnunkn15>{{cite journal|author-link4=Sunney Chan |vauthors=Schultz BE, Ye B, Li X, Chan SI | title = Electronic Paramagnetic Resonance and Magnetic Properties of Model Complexes for Binuclear Active Sites in Hydrolase Enzymes | journal = Inorg. Chem. | volume = 36 |issue=12 | pages = 2617–2622 | year=1997 | doi = 10.1021/ic960988r }}</ref> Katalitski mehanizmi enzima hidrolaze uveliko zavise od identiteta mostovnog liganda,<ref name=isbnunkn16>{{cite journal |vauthors=Korendovych IV, Kryatov SV, Reiff WM, Rybak-Akimova EV | title = Diiron(II) mu-aqua-mu-hydroxo model for non-heme iron sites in proteins | journal = Inorg Chem | volume = 44 | issue = 24 | pages = 8656–8 |date=novembar 2005 | pmid = 16296818 | doi = 10.1021/ic051739i }}</ref> što može biti izazovno odrediti zbog teškoća proučavanja atoma vodika putem [[rendgenska kristalografija|kristalografije X-zraka]].

Ostaci histidina prikazani u mehanizmu desno, H178 i H79, konzervirani su u svim MetAP-ovima (MetAP1 i MetAP2) sekvenciranim do danas, što sugerira da je njihovo prisustvo važno za katalitsku aktivnost.<ref name=isbnunkn40>{{cite journal |vauthors=Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ, Ye QZ | title = Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity | journal = J. Biol. Chem. | volume = 279 | issue = 20 | pages = 21128–34 |date=maj 2004 | pmid = 14976199 | doi = 10.1074/jbc.M401679200 | doi-access = free }}</ref> Na osnovu rendgenskih kristalografskih podataka, predloženo je da histidin 79 (H79) pomaže u pozicioniranju ostatka metionina u aktivnom mjestu i prijenosu protona na novoizloženi [[N-terminal]]ni amin.<ref name=isbnunkn7 /> Lowther et al. predložili su dva moguća mehanizma za MetAP2 u ''E. coli'', prikazana desno.<ref name=isbnunkn9 />

== Funkcija ==
Metionin aminopeptidaza 2, član porodice dimetalohidrolaze, je [[citosol]]ni metaloenzim koji katalizuje hidrolitsko uklanjanje N-terminalnih [[metionin]]skih ostataka iz nastalih [[protein]]a.<ref name=isbnunkn1>{{cite journal | vauthors = Bennett B, Holz RC | title = EPR Studies on the Mono- and Dicobalt(II)-Substituted Forms of the Aminopeptidase from Aeromonas proteolytica. Insight into the Catalytic Mechanism of Dinuclear Hydrolases | journal = J. Am. Chem. Soc. | volume = 119 | issue = 8 | pages = 1923–1933 | year=1997 | doi = 10.1021/ja963021v }}</ref><ref name=isbnunkn2>{{cite journal |vauthors=Johansson FB, Bond AD, Nielsen UG, Moubaraki B, Murray KS, Berry KJ, Larrabee JA, McKenzie CJ | title = Dicobalt II-II, II-III, and III-III complexes as spectroscopic models for dicobalt enzyme active sites | journal = Inorg Chem | volume = 47 | issue = 12 | pages = 5079–92 |date=juni 2008 | pmid = 18494467 | doi = 10.1021/ic7020534 }}</ref><ref name=isbnunkn3>{{cite journal |vauthors=Larrabee JA, Leung CH, Moore RL, Thamrong-nawasawat T, Wessler BS | title = Magnetic circular dichroism and cobalt(II) binding equilibrium studies of Escherichia coli methionyl aminopeptidase | journal = J. Am. Chem. Soc. | volume = 126 | issue = 39 | pages = 12316–24 |date=oktobar 2004 | pmid = 15453765 | doi = 10.1021/ja0485006 }}</ref>

* peptid-metionin <math>\rightleftharpoons</math> peptid + metionin.

MetAP2 se nalazi u svim organizmima i posebno je važan zbog svoje kritične uloge u obnavljanju tkiva i degradaciji proteina.<ref name=isbnunkn1 /> Nadalje, MetAP2 je od posebnog interesa jer enzim ima ključnu ulogu u [[angiogeneza|angiogenezi]], rastu novih krvnih sudova, koji je neophodan za napredovanje bolesti uključujući solidni tumorski [[karcinom]] i [[reumatoidni artritis]].<ref name=isbnunkn4>{{cite journal | author = Folkman J | title = Angiogenesis in cancer, vascular, rheumatoid and other disease | journal = Nat. Med. | volume = 1 | issue = 1 | pages = 27–31 |date=januar 1995 | pmid = 7584949 | doi = 10.1038/nm0195-27 | s2cid = 5924813 }}</ref> MetAP2 je također meta dvije grupe prirodnih antiangiogenih proizvoda, [[ovalicin]] i [[fumagilin]] i njihovih analoga kao što je [[beloranib]].<ref name=isbnunkn7>{{cite journal |vauthors=Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM | title = The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 12 | pages = 6099–103 |date=juni 1997 | pmid = 9177176 | pmc = 21008 | doi = 10.1073/pnas.94.12.6099 | bibcode = 1997PNAS...94.6099S | doi-access = free }}</ref><ref name=isbnunkn9>{{cite journal |vauthors=Lowther WT, McMillen DA, Orville AM, Matthews BW | title = The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 21 | pages = 12153–7 |date=oktobar 1998 | pmid = 9770455 | pmc = 22800 | doi = 10.1073/pnas.95.21.12153  | bibcode = 1998PNAS...9512153L | doi-access = free }}</ref><ref name="Taunton">{{cite journal | author = Taunton J | title = How to starve a tumor | journal = Chem. Biol. | volume = 4 | issue = 7 | pages = 493–6 |date=juli 1997 | pmid = 9263636 | doi = 10.1016/S1074-5521(97)90320-3  | doi-access = free }}</ref><ref name=isbnunkn8>{{cite journal |vauthors=Griffith EC, Su Z, Turk BE, Chen S, Chang YH, Wu Z, Biemann K, Liu JO | title = Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin | journal = Chem. Biol. | volume = 4 | issue = 6 | pages = 461–71 |date=juni 1997 | pmid = 9224570 | doi = 10.1016/S1074-5521(97)90198-8 | doi-access = free }}</ref>

Dok su prethodne studije pokazale da MetAP2 katalizira uklanjanje [[N-terminal]]nih ostataka metionina ''[[in vitro]]'', funkcija ovog enzima ''[[in vivo]]'' može biti složenija. Naprimjer, postoji značajna [[korelacija]] između inhibicije enzimske aktivnosti MetAP2 i inhibicije rasta ćelija, što implicira enzim u [[Proliferacija ćelija|proliferaciji]] [[endotel]]nih ćelija.<ref name=isbnunkn8/> Iz tog razloga, MetAP2 izdvojen je  kao potencijalna metu za inhibiciju angiogeneze. Štaviše, studije su pokazale da MetAP2 pročišćava i stupa u interakciju sa α podjedinicom eukariotskog inicijacionog faktora 2 ([[eIF2]]), proteina koji je neophodan za sintezu proteina ''in vivo''.<ref name=isbnunkn17>{{cite journal |vauthors=Wu S, Rehemtulla A, Gupta NK, Kaufman RJ | title = 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 | journal = Biochemistry | volume = 35 | issue = 25 | pages = 8275–80 |date=juni 1996 | pmid = 8679583 | doi = 10.1021/bi953028+ }}</ref> Konkretno, MetAP2 štiti eIF-2α od inhibicije [[fosforilacije]] od enzima eIF-2α [[kinaze]], inhibira [[RNK]]-zavisnu protein kinazu (PKR) kataliziranu fosforilaciju eIF-2 R-podjedinice, a također preokreće PKR- posredovanu inhibiciju sinteze proteina u intaktnim ćelijama.

== Klinički značaj ==
[[slika:MetAP2 bound to fumagillin.png|thumb|upright=2.2|left|Slika 3: Fumagilin (zeleni i crveni) vezan za aktivno mjesto ljudskog MetAP2 (višebojno, sa cijan, ljubičastom i ružičastom koja odgovara heliksimama, listovima i petljama), s prikazanim dimetalnim ionima (plavo).]]
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Brojne studije impliciraju MetAP2 u angiogenezi.<ref name=isbnunkn13/><ref name=isbnunkn8/><ref name=isbnunkn27>{{cite journal |vauthors=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 | title = An orally delivered small-molecule formulation with antiangiogenic and anticancer activity | journal = Nat. Biotechnol. | volume = 26 | issue = 7 | pages = 799–807 |date=juli 2008 | pmid = 18587385 | pmc = 2803109 | doi = 10.1038/nbt1415 }}</ref><ref name=isbnunkn28>{{cite journal | author = Sato Y | title = Aminopeptidases in Health and Disease: Role of Aminopeptidase in Angiogenesis | journal = Biol. Pharm. Bull. | volume = 27 | issue = 6 | pages = 772–776 | year=2004 | doi = 10.1248/bpb.27.772 | pmid = 15187415 | doi-access = free }}</ref><ref name=isbnunkn29>{{cite journal |vauthors=Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO | title = Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo | journal = Chem. Biol. | volume = 16 | issue = 2 | pages = 193–202 |date=februar 2009 | pmid = 19246010 | doi = 10.1016/j.chembiol.2009.01.006 | doi-access = free }}</ref> Konkretno, pokazalo se da [[kovalentna veza|kovalentno]] vezivanje ovalicinskog ili fumagilinskog [[epoksid]]nog ostatka na aktivnom mjestu [[histidin]]skog ostatka MetAP2 inaktivira enzim, čime se inhibira [[angiogeneza]]. Međutim, način na koji MetAP2 reguliše angiogenezu tek treba da se utvrdi, tako da je potrebno dalje istraživanje, kako bi se potvrdilo da antiangiogena aktivnost direktno proizlazi iz inhibicije MetAP2. Ipak, kako rast i [[metastaze]] solidnih tumora u velikoj mjeri ovise o angiogenezi, fumagilin i njegovi analozi—uključujući [[TNP-470]], [[kaplostatin]] i [[beloranib]]—kao i ovalicin predstavljaju potencijalne agense protiv raka.<ref name=isbnunkn28/><ref name=isbnunkn29/>

Štaviše, sposobnost MetAP2 da smanji vitalnost ćelija u prokariotskim i malim eukariotskim organizmima učinila ga je metom za antibakterijske agense.<ref name=isbnunkn8 /> Do sada se pokazalo da i fumagilin i TNP-470 imaju i antimalarijsko djelovanje i kod ''in vitro'' i ''in vivo'' primjene, i [[fumarranol]], još jedan analog fumagilina, predstavlja obećavajuću prednost.<ref name=isbnunkn29/>

METAP2 inhibitor beloranib (ZGN-433) pokazao je djelotvornost u smanjenju tjelesne težine kod izrazito [[gojaznost|gojaznih]] osoba.<ref name="urlZafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity - Drugs.com MedNews">{{cite web | url = https://www.drugs.com/clinical_trials/zafgen-announces-positive-topline-phase-1b-data-zgn-433-obesity-10955.html | title = Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity  | date = 1. 1. 2011 | work = MedNews | publisher = Drugs.com | access-date = 13. 4. 2011 }}</ref> MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat, leading to substantial loss of body weight. Development of beloranib was halted in 2016 after deaths during clinical trials.<ref name=nasdaq>{{cite news | url = http://www.nasdaq.com/article/zafgen-halts-development-of-beloranib-to-cut-jobs-by-34-cm651992 | publisher = nasdaq.com | title = Zafgen Halts Development of Beloranib, to Cut Jobs by ~34% | date = 20. 7. 2016}}</ref>

== Interakcije ==
Pokazalo se da METAP2  ima [[interakcija protein-protein|interakcije]] sa [[protein-kinaza R|protein-kinazom R]].<ref name="pmid11123929">{{cite journal |vauthors=Gil J, Esteban M, Roth D | title = In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67 | journal = Biochemistry | volume = 39 | issue = 51 | pages = 16016–25 |date=decembar 2000 | pmid = 11123929 | doi = 10.1021/bi001754t }}</ref>
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==Reference==
{{reflist | colwidth = 35em}}

==Dopunska literatura==
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*{{cite journal  |vauthors=Datta B, Datta R, Mukherjee S, Zhang Z |title=Increased phosphorylation of eukaryotic initiation factor 2alpha at the G2/M boundary in human osteosarcoma cells correlates with deglycosylation of p67 and a decreased rate of protein synthesis |journal=Exp. Cell Res. |volume=250 |issue= 1 |pages= 223–30 |year= 1999 |pmid= 10388536 |doi= 10.1006/excr.1999.4508 }}
*{{cite journal  |vauthors=Gil J, Esteban M, Roth D |title=In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67 |journal=Biochemistry |volume=39 |issue= 51 |pages= 16016–25 |year= 2001 |pmid= 11123929 |doi=10.1021/bi001754t  }}
*{{cite journal |vauthors=Catalano A, Romano M, Robuffo I, Strizzi L, Procopio A | title = Methionine aminopeptidase-2 regulates human mesothelioma cell survival: role of Bcl-2 expression and telomerase activity | journal = Am. J. Pathol. | volume = 159 | issue = 2 | pages = 721–31 |date=august 2001 | pmid = 11485930 | pmc = 1850571 | doi = 10.1016/S0002-9440(10)61743-9 }}
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*{{cite journal  |vauthors=Datta R, Tammali R, Datta B |title=Negative regulation of the protection of eIF2alpha phosphorylation activity by a unique acidic domain present at the N-terminus of p67 |journal=Exp. Cell Res. |volume=283 |issue= 2 |pages= 237–46 |year= 2003 |pmid= 12581743 |doi=10.1016/S0014-4827(02)00042-3  }}
*{{cite journal |vauthors=Serero A, Giglione C, Sardini A, Martinez-Sanz J, Meinnel T | title = An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway | journal = J. Biol. Chem. | volume = 278 | issue = 52 | pages = 52953–63 |date=decembar 2003 | pmid = 14532271 | doi = 10.1074/jbc.M309770200 | doi-access = free }}
*{{cite journal |vauthors=Selvakumar P, Lakshmikuttyamma A, Kanthan R, Kanthan SC, Dimmock JR, Sharma RK | title = High expression of methionine aminopeptidase 2 in human colorectal adenocarcinomas | journal = Clin. Cancer Res. | volume = 10 | issue = 8 | pages = 2771–5 |date=april 2004 | pmid = 15102683 | doi = 10.1158/1078-0432.CCR-03-0218 | doi-access = free }}
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