Synthesis and Aminoacyl-tRNA Synthetase Inhibitory Activity of Prolyl Adenylate Analogs

✍ Scribed by Donald Heacock; Craig J. Forsyth; Kiyotaka Shiba; Karin Musier-Forsyth

• Publisher: Elsevier Science
• Year: 1996
• Tongue: English
• Weight: 246 KB
• Volume: 24
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1006/bioo.1996.0025

✦ Synopsis

Two nonhydrolyzable prolyl adenylate analogs, 5Ј-O-[N-(L-prolyl)-sulfamoyl]adenosine (L-PSA) and 5Ј-O-[N-(D-prolyl)-sulfamoyl]adenosine (D-PSA), were prepared in three steps from 2Ј,3Ј-di-O-isopropylideneadenosine. Both of these compounds inhibited the in vitro activity of Escherichia coli and human prolyl-tRNA synthetase (ProRS). The human enzyme used in this study was derived from the carboxy-terminal domain of the multifunctional human EPRS gene. The K ATP i values for L-PSA, determined using the ATP-PP i exchange assay, are very similar for both synthetases (Ȃ 1-2 nM). The K Pro i values, on the other hand, vary approximately seven-fold between the two synthetases (0.6 nM for human and 4.3 nM for E. coli). The K i values measured for the D-PSA analog are much higher (51-470 nM) for all cases examined; however, the same species-specific differences are observed with respect to K Pro i . These results indicate possible structural differences in or near the active sites of the two enzymes that may be exploited in the future design of compounds that function as speciesspecific synthetase inhibitors in vivo.