Disease relevance of METAP1

• These findings suggest that there are two cobalt-dependent MetAP families, presently composed of the prokaryote and yeast sequences (and represented by the E. coli structure) (type I), on the one hand, and by human MetAP, the yeast open reading frame, and the partial prokaryotic sequence (type II), on the other [1].
• The 1.15A crystal structure of the Staphylococcus aureus methionyl-aminopeptidase and complexes with triazole based inhibitors [2].
• We demonstrate that the Salmonella typhimurium methionine aminopeptidase is totally inactive on an N-formyl-methionyl peptide in vitro, and present a detailed characterization of the substrate specificity of this key enzyme by use of a very sensitive and quantitative assay [3].
• These results have demonstrated the possibility of developing MetAP inhibitors as antibacterial agents with minimum human toxicity [4].
• Antisera against different Ehrlichiae recognize an immunodominant, cross-reacting approximately 28 kDa surface antigen defined as the MAP1 in Cowdria ruminantium [5].

High impact information on METAP1

• Fumagillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dimensional structure also indicates the likely determinants of this specificity [6].
• Methionine aminopeptidase-1: the MAP of the mitochondrion [7]?
• In addition, the linkage of tau and MAP1 turnover with the state of microtubule polymerization amplifies any change in their rate of synthesis, since tau and MAP1 promote microtubule polymerization [8].
• We have found that contrary to previous suggestions, the major MAPs of adult brain, MAP1 and MAP2, are minor components of PC12 cells [9].
• Nerve growth factor induces neurite process formation in pheochromacytoma (PC12) cells and causes the parallel increase in levels of the microtubule-associated proteins, tau and MAP1, as well as increases in tubulin levels [8].

Chemical compound and disease context of METAP1

• The combination of these data suggests that the in vivo metal ions for the MetAP enzyme from E. coli are likely Fe(II) ions [10].

Biological context of METAP1

• However, human MetAP was found to be much more similar to a yeast open reading frame that differed markedly from the previously reported yeast MetAP [1].
• The C-terminal portion representing the catalytic domain shows limited identity with MetAP sequences from various prokaryotes and yeast, while the N terminus is rich in charged amino acids, including extended strings of basic and acidic residues [1].
• The most potent of these compounds contained a singly-substituted triazole moiety which exhibited an IC50 of 8 nM (95% confidence limits 5 to 13 nM) and was highly selective for MetAP-2 over MetAP-1 (approximately 60-fold difference in IC50 values) [11].
• Comparison of the Type I enzyme with the previously reported complex of ovalicin with Type II MetAP shows that the active site of the former is reduced in size and would incur steric clashes with the bound inhibitor [12].
• The dependence of cell growth on methionine aminopeptidase (MetAP) function in bacteria and yeast is firmly established [13].

Anatomical context of METAP1

• Both drug-sensitive and drug-insensitive cell lines express MetAP1 and MetAP2, indicating that drug sensitivity in mammalian cells is not simply due to the absence of compensating MetAP activity [14].
• The degradation of tau, MAP1, and both tubulin polypeptides, however, are stimulated by microtubule depolymerization caused by colchicine, or nerve growth factor removal [8].
• In contrast MAP1, which is characteristic of mature neurons, does not increase during PC12 cell differentiation [9].
• High expression of methionine aminopeptidase type 2 in germinal center B cells and their neoplastic counterparts [15].
• Our observations suggest that MAP1 B-phos plays an important role in regeneration processes in the central nervous system (CNS) of the fish [16].

Associations of METAP1 with chemical compounds

• Human methionine aminopeptidase type 2 (hMetAP-2) was identified as the molecular target of anti-angiogenic agents such as fumagillin and its analogues [17].
• Human methionine aminopeptidase type 2 in complex with L- and D-methionine [17].
• Although the binding of S100A4 did not affect the in vitro methionine aminopeptidase activity of MetAP2, the cytochemical observation suggests a possible involvement of S100A4 in the regulation of MetAP2 activity through changing its localization, thereby modulating the N-terminal methionine processing of nascent substrates [18].
• Mutation of this residue to alanine resulted in an ovalicin-sensitive MetAP-1 allele, demonstrating that an alanine at this position is critical for inhibition by ovalicin [19].
• Alignment of human MetAP-2 with human MetAP-1, which is naturally ovalicin-resistant, revealed that the analogous residue in MetAP-1 is also a threonine [19].

Physical interactions of METAP1

• In the second assay method, the MetAP reaction is coupled to a prolyl aminopeptidase reaction using Met-Pro-p-nitroanilide as substrate [20].

Other interactions of METAP1

• Model building established that human MetAP (p67) could be readily accommodated into the Escherichia coli MetAP structure and that the Co2+ ligands were fully preserved [1].
• MAP-1 and MAP-2 occurred in all SG cells but only MAP-1 was found in the nerve fibres [21].
• This novel protein, named laeverin, has a peptidase M1 motif containing a zinc-binding active site [22].
• Authentic soluble human beta-globin chains were produced in Escherichia coli using an expression plasmid (pHE2beta) containing full-length cDNAs coding for human beta-globin chain and methionine aminopeptidase [23].
• In the two larger proteins tested (myoglobin, 32 core amino acids; methionine aminopeptidase, 63 core amino acids), sequences with corresponding side-chain conformations remarkably similar to that of native were predicted [24].

Analytical, diagnostic and therapeutic context of METAP1

• To study this in greater detail, MAP1.2 in PC12 cell lysates was resolved by SDS-PAGE in gels containing 3.25% acrylamide/4 M urea and identified by comigration with material immunoprecipitated from the lysates by MAP1 antibodies [25].
• Immunofluorescence for MAP-1 occurred in the supporting cells of the cristae and maculae interpreted to be localized in the apical region adjacent to the sensory cells [26].

References