European Journal of Medicinal Chemistry p. 252 - 264 (2019)
Update date:2022-08-29
Topics:
De Ruysscher, Dries
Pang, Luping
De Graef, Steff
Nautiyal, Manesh
De Borggraeve, Wim M.
Rozenski, Jef
Strelkov, Sergei V.
Weeks, Stephen D.
Van Aerschot, Arthur
The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS)and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA)compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 ? crystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.
View MoreContact:+86-20-32051076
Address:1105,Building A, International Business Incubator,Science City
Hangzhou Eastbiopharm Co.,Ltd.
Contact:+86-571-88931780
Address:Hangzhou,China
Pengchen New Material Technology Co., Ltd.
Contact:+86-512-63680537
Address:99.6 km of national road 318, Meiyan Community,Pingwang Town, Wujiang District, Suzhou 215225
website:http://www.finetechnology-ind.com
Contact:86-27-87465837
Address:wuhan
Weifang Arylchem Chemical Co., LTD
Contact:86-536-5217866
Address:Development Zone, Shouguang, Shandong Province
Doi:10.1016/S0040-4039(00)00840-6
(2000)Doi:10.1080/00958972.2010.487938
(2010)Doi:10.1021/jp992999m
(2000)Doi:10.1002/ardp.19813140306
(1981)Doi:10.1021/ja00065a001
(1993)Doi:10.1080/004982500406462
(2000)