Investigation of bioisosteric effects on the interaction of substrates/ inhibitors with the methionyl-tRNA synthetase from Escherichia coli.

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Vaughan MD, Sampson PB, Daub E, Honek JF

Investigation of bioisosteric effects on the interaction of substrates/ inhibitors with the methionyl-tRNA synthetase from Escherichia coli.

Med Chem. 2005 May;1(3):227-37.

PubMed ID

16787318 [ View in PubMed

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Abstract

Aminoacyl-tRNA synthetases catalyze the stepwise coupling of specific amino acid substrates to their cognate tRNAs. The first intermediate formed in this process is the aminoacyl-adenylate, which then subsequently reacts with the 3'-terminus of the cognate tRNA to transfer the amino acid to the tRNA. This overall reaction is critical for protein biosynthesis and is quintessential to the viability of all organisms. Therefore, the selective inhibition of bacterial amino acid-tRNA synthetases is the focus of intense current interest for the development of novel antibacterial agents. In order to elucidate some of the critical factors involved in recognition and binding of potential inhibitors to these bacterial systems, the current report has focused on the methionyl-tRNA synthetase from Escherichia coli. This enzyme has been studied with two sets of bioisosteric replacements in the methionine and methionyl-adenylate structures. Replacements of the carboxyl group of methionine with the phosphinic and phosphonic acid moieties were used to probe the effects of including potential transition state analogs on enzyme inhibition. The contributions of the aminoacyl-adenylate structure and the effect that fluorination has on inhibitory activity were investigated utilizing 5'-O-[(L-methionyl)-sulfamoyl]adenosine and 5'-O-[(S-trifluoromethyl-L-homocysteinyl)-sulfamoyl]adenosine. The K(i) values for these compounds were determined to be 0.4 mM, 1.2 mM, 0.25 nM and 2.4 nM respectively. A discussion of this data in relation to structural information provided by the recent determination of the three-dimensional structures of the E. coli enzyme with several of these compounds is presented.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Methionine	Methionine--tRNA ligase, cytoplasmic	Protein	Humans	Unknown	Substrate	Details