Disease relevance of ECs2920

• In the 676-amino acid Escherichia coli methionyl-tRNA synthetase (MetRS), interactions with the methionine tRNA anticodon are sensitive to substitutions at a specific location on the surface of the C-terminal domain of this protein of known three-dimensional structure [1].
• Mycobacterium tuberculosis methionyl-tRNA synthetase (MetRS) has been cloned and characterized [2].
• In the present study, site-directed mutagenesis was used to probe the role of these conserved residues in the case of the Bacillus stearothermophilus methionyl-tRNA synthetase [3].
• The three-dimensional quantitative structure-activity relationships of 57 2-[(aminopropyl)amino]-4(1H)-quinolinone analogues as Staphylococcus aureus methionyl-tRNA synthetase (MetRS) inhibitors with excellent antibacterial profile were investigated and docking studies were performed [4].
• Results: We determined the crystal structure of the class Ia methionyl-tRNA synthetase (MetRS) at 2.0 A resolution, using MetRS from an extreme thermophile, Thermus thermophilus HB8 [5].

High impact information on ECs2920

• Screening of a saturation mutagenesis library of the E. coli methionyl-tRNA synthetase (MetRS) led to the discovery of three MetRS mutants capable of incorporating the long-chain amino acid azidonorleucine into recombinant proteins with modest efficiency [6].
• Lysidine, a lysine-combined modified cytidine, is exclusively located at the anticodon wobble position (position 34) of eubacterial tRNA(Ile)(2) and not only converts the codon specificity from AUG to AUA, but also converts the aminoacylation specificity from recognition by methionyl-tRNA synthetase to that by isoleucyl-tRNA synthetase (IleRS) [7].
• Multiple individual replacements at this location do not disrupt enzyme stability, indicating this segment is on the surface, as in the MetRS structure [1].
• Homocysteine (Hcy) editing by methionyl-tRNA synthetase results in the formation of Hcy-thiolactone and initiates a pathway that has been implicated in human disease [8].
• Upon chemical modification of the 3 Cys residues of T. thermophilus MetRS with sodium p-(hydroxymercuri)phenylsulfonate, one Zn2+ ion was released from one subunit of the molecule, as monitored with 4-(2-pyridylazo)resorcinol [9].

Chemical compound and disease context of ECs2920

• A cyclic sulfonium compound, S-methyl homocysteine thiolactone (SMHT), is formed from methionine during in vitro tRNA aminoacylation catalyzed by Escherichia coli methionyl-tRNA synthetase [10].
• Four different structural regions of Escherichia coli tRNAfMet have been covalently coupled to E. coli methionyl-tRNA synthetase (MetRS) by using a tRNA derivative carrying a lysine-reactive cross-linker [11].

Biological context of ECs2920

• Cyclization of methionine, reminiscent of cyclization of homocysteine during editing, illustrates the limited ability of methionyl-tRNA synthetase to discriminate against the cognate methionine at the editing site designed for the noncognate homocysteine [10].
• Binding of methionine to methionyl-tRNA synthetase (MetRS) is known to promote conformational changes within the active site [12].
• The obtained 3D model was used to direct mutations against dimerization of Escherichia coli MetRS [13].

Anatomical context of ECs2920

• As in the threonine system, the interaction of MetRS with the CAU operator occludes ribosome binding to its loading site [14].

Associations of ECs2920 with chemical compounds

• Complexes with methionyl adenylate analogues illustrate the shielding by MetRS of the region joining the methionine and adenosine moieties [12].
• In TyrRS, these residues are close to the adenylate binding site, and in MetRS to the Mg2+-ATP binding site [15].
• Amino acid analysis indicated that the major product was an octadecapeptide cross-linked to tRNA(mMet) through lysine residue 596 in the primary sequence of MetRS [16].
• Complete inactivation corresponded to the incorporation of 0.98 mol of AP3-PL/mol of monomeric trypsin-modified MetRS [17].
• Primary sequence comparisons of class I aminoacyl-tRNA synthetases show that all but one member of this group of enzymes has an aspartic acid residue at the site corresponding to Asp52 in MetRS [18].

Other interactions of ECs2920

• AP3-PL-labeled Lys-335 of MetRS and Lys-557 of ValRS belong to the consensus tRNA CCA-binding Lys-Met-Ser-Lys-Ser sequence [Hountondji, C., Dessen, P., & Blanquet, S. (1986) Biochimie 68, 1071-1078].(ABSTRACT TRUNCATED AT 250 WORDS)[17]
• A series of sulfamate surrogates of methionyl and isoleucyl adenylate have been investigated as MetRS and IleRS inhibitors by modifications of the sulfamate linker and adenine moieties [19].

Analytical, diagnostic and therapeutic context of ECs2920

• In the present work, we have examined the function of three amino acid residues in the active site of Escherichia coli methionyl-tRNA synthetase (MetRS) in substrate binding and catalysis using site-directed mutagenesis [18].
• Sequence analysis showed that the peptides were cross-linked to tRNAfMet through lysine residues 402, 439, 465, and 640 in the primary sequence of MetRS [11].

References