Disease relevance of MAP1

• Mutation of Gln356 (Gln233 in E. coli MetAP) to alanine results in a catalytic efficiency about one-third that of native with normal substrates but which can cleave methionine from substrates with penultimate histidine, asparagine, glutamine, leucine, methionine, phenylalanine, and tryptophan [1].

High impact information on MAP1

• Overexpression of HsMetAP1, but not HsMetAP2, conferred resistance of cells to the inhibitors, and the inhibitors caused retention of N-terminal methionine of a known MetAP substrate, suggesting that HsMetAP1 is the cellular target for the inhibitors [2].
• Transformants of map1 null cells expressing MAP2 in a high-copy-number plasmid contained 3- to 12-fold increases in Met-AP activity on different peptide substrates [3].
• Overexpression of map1 resulted in enhanced transcription of cell-type-specilic genes, but the range of genes affected by Map1 was restricted by the mating type of the cell [4].
• Additionally, Gfa1 will be a relevant target in therapeutic or physiological applications in which MetAP activity is inhibited [5].
• MAP-1 and IAP-1, two novel AAA proteases with catalytic sites on opposite membrane surfaces in mitochondrial inner membrane of Neurospora crassa [6].

Biological context of MAP1

• Ribosome profiles of map1 null expressing wild-type MetAP1 or one of three zinc finger mutants were compared [7].
• Results of yeast two-hybrid analysis suggested that Map1 may physically interact with Mat1-Pc, the product of the h(+)-specific mating-type gene mat1-Pc [4].
• Methionine aminopeptidase (MetAP), in two isoenzymic forms, is responsible for hydrolysis of the initiator methionine residues from the majority of newly synthesized proteins [8].

Anatomical context of MAP1

• Furthermore, unlike the case for the prokaryotic gene, the deletion of the yeast MAP1 gene is not lethal, suggesting for the first time that alternative NH2-terminal processing pathway(s) exist for cleaving methionine from nascent polypeptide chains in eukaryotic cells [9].

Associations of MAP1 with chemical compounds

• Limited proteolysis of intact yeast methionine aminopeptidase (MAP1) with trypsin releases a 34 kDa fragment whose NH2-terminal sequence begins at Asp70, immediately following Lys69 [10].
• In the presence of physiological concentrations of reduced glutathione (GSH), Co-MetAP I is inactive, while the activity of Zn-MetAP I is increased more than 1.7-fold over Zn-MetAP I assayed in the absence of GSH [11].
• The cis-fumagillin methyl ester, a stereoisomer of fumagillin methyl ester at the C2'-C3' position of the aliphatic side chain, selectively inhibited growth of the map1 mutant yeast strain (MetAP1 deletion strain) at a concentration as low as 1 ng [12].
• Some of the pyridine-2-carboxylic acid derivatives (compound 2 and 3) had selective inhibition of the growth of map2 deletion yeast and weak inhibition on wild-type yeast growth, while no inhibition on map1 deletion yeast [13].
• They represent small-molecule MetAP inhibitors with novel structures different from alkylating fumagillin derivatives and peptidic bestatin-based MetAP inhibitor [14].

Regulatory relationships of MAP1

• Overexpression of MetAP2 (H174A) under the strong GPD promoter in a yeast map1 null strain was lethal, whereas overexpression under the weaker GAL1 promoter slightly inhibited map1 null growth [15].

Other interactions of MAP1

• The map2 null strain, like the map1 null strain, is viable but with a slower growth rate [3].

Analytical, diagnostic and therapeutic context of MAP1

• Using site-directed mutagenesis, recombinant yeast MetAP I derivatives that are able to cleave N-terminal methionine from substrates that have larger penultimate residues have been expressed [1].

References