Inhibitors of glutamine synthetase and their potential application in medicine.
Glutamine synthetase (E.C. 6.3.1.2) - an enzyme catalyzing formation of glutamine from glutamate and ammonium ion, is one of the most important enzymes in nitrogen metabolism. Due to glutamine synthetase activity, inorganic nitrogen is incorporated in the cell metabolism and is further used in biosynthesis of several highly important metabolites. The first part of the review presents the long-dating research on inhibitors of glutamine synthetase which started with the discovery of methionine sulfoximine in 1949. Since that time several inhibitors of this enzyme, classified in the following groups: derivatives of methionine sulfoximine, phosphorus containing analogues of glutamic acid, bisphosphonates and miscellaneous inhibitors, have been developed and described. Analysis of their structure-activity relationships is presented in some detail. The second part of the paper is dedicated to potential medical application of glutamine synthetase inhibitors, which proved to act as effective anti-tuberculosis agents with high selectivity towards the pathogenic bacteria. Moreover, it was also shown that glutamine synthetase inhibitors could be successfully applied in cancer therapy.
Berlicki
Łukasz
Ł
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspiańskiego 27, Wrocław, Poland. lukasz.berlicki@pwr.wroc.pl
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004164:Diphosphonates / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009584:Nitrogen / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D005974:Glutamate-Ammonia Ligase; D009584:Nitrogen