METAP2

Source: Wikipedia, the free encyclopedia.
METAP2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000111142

ENSMUSG00000036112

UniProt

P50579

O08663

RefSeq (mRNA)

NM_006838
NM_001317182
NM_001317183
NM_001330246

NM_019648

RefSeq (protein)

NP_001304111
NP_001304112
NP_001317175
NP_006829

NP_062622

Location (UCSC)Chr 12: 95.47 – 95.52 MbChr 10: 93.69 – 93.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.[5][6]

Methionine aminopeptidase 2, a member of the dimetallohydrolase family, is a

proteins.[7][8][9]

  • peptide-methionine peptide + methionine

MetAP2 is found in all organisms and is especially important because of its critical role in tissue repair and protein degradation.

cancers and rheumatoid arthritis.[10] MetAP2 is also the target of two groups of anti-angiogenic natural products, ovalicin and fumagillin, and their analogs such as beloranib.[11][12][13][14]

Structure

In living organisms, the start

E. coli (prokaryote), an enzyme called formylmethionine deformylase can cleave the formyl group, leaving just the N-terminal methionine residue. For proteins with small, uncharged penultimate N-terminal residues, a methionine aminopeptidase can cleave the methionine residue.[7]
The number of
S. cerevisiae, MetAP2 is 22 percent homologous with the sequence of MetAP1; MetAP2 is highly conserved between S. cerevisiae and humans.[16]
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,

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

crystallized
MetAP2 either in the presence of Zn(II) or Co(II) (see PDB database).

Mechanism

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.[27]

The bridging water or hydroxide ligand acts as a nucleophile during the hydrolysis reaction, but the exact mechanism of catalysis is not yet known.[10][19][28] The catalytic mechanisms of hydrolase enzymes depend greatly on the identity of the bridging ligand,[29] 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.[30] 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.[12] Lowther and Colleagues have proposed two possible mechanisms for MetAP2 in E. coli, shown at the right.[14]

Function

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.[13] For this reason, cancer researchers 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.[31] 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.

covalent binding of either the ovalicin or fumagillin epoxide moiety to the active site histidine residue of MetAP2 has been shown to inactivate the enzyme, thereby inhibiting angiogenesis. The way in which MetAP2 regulates angiogenesis has yet to be established, however, such that further study is required to validate that antiangiogenic activity results directly from MetAP2 inhibition. Nevertheless, with both the growth and metastasis of solid tumors depending heavily on angiogenesis, fumagillin and its analogs—including evexomostat, TNP-470, caplostatin, and beloranib—as well as ovalicin represent potential anticancer agents.[33][34]
Moreover, the ability of MetAP2 to decrease cell viability in prokaryotic and small eukaryotic organisms has made it a target for antibacterial agents.[13] 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.[34]

The fumagillin-derived METAP2 inhibitor beloranib (ZGN-433, CDK-732) has shown efficacy in reducing weight in severely obese subjects.[35] MetAP2 inhibitors work by re-establishing insulin sensitivity and balance to the ways the body metabolizes fat, leading to substantial loss of body weight. Development of beloranib was halted in 2016 after two deaths during clinical trials for patients with Praeder-Willi Syndrome.[36] A polymer-drug conjugate of a novel MetAP2 inhibitor called evexomostat being developed by SynDevRx, Inc. entered clinical development for late-stage cancer patients in 2016. Phase 1 dose escalation studies were completed in 2020. In 2022, SynDevRx initiated a Phase 2 clinical study of evexomostat in collaboration with Memorial Sloan Kettering Cancer Center of New York to assess the safety and efficacy in recurrent, metastatic triple-negative breast cancer in combination with the drug eribulin (Halaven(R)). In 2023, SynDevRx initiated another Phase 2 clinical study of evexomostat in combination with the alpelisib (Piqray (R)) and fulvestrant (Faslodex (R)) in metastatic HR+/Her2- breast cancer patients.

Interactions

METAP2 has been shown to

interact with Protein kinase R.[37]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000111142 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036112 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  35. ^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 2011-01-01. Retrieved 2011-04-13.
  36. ^ "Zafgen Halts Development of Beloranib, to Cut Jobs by ~34%". nasdaq.com. July 20, 2016.
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Further reading
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