5jyp
Allosteric inhibition of Kidney Isoform of Glutaminase
Structural highlights
FunctionGLSK_HUMAN Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity. Publication Abstract from PubMedCancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion of glutamine to glutamate, is gaining increasing attention as a potential drug target. Small-molecule inhibitors such as BPTES and CB-839, which target the allosteric site of glutaminase with high specificity, demonstrate immense promise as anti-tumor drugs. Here, we report the study of a new BPTES analog, N,N'-(5,5'-(trans-cyclohexane-1,3-diyl)bis(1,3,4-tiadiazole-5,2-diyl))bis(2-pheny lacetamide) (trans-CBTBP), and compared its inhibitory effect against that of CB-839 and BPTES. We show that CB-839 has a 30- and 50-fold lower IC50 than trans-CBTBP and BPTES, respectively. To explore the structural basis for the differences in their inhibitory efficacy, we solved the complex structures of cKGA with 1S, 3S-CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1S, 3S-CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers. Structural basis for exploring the allosteric inhibition of human kidney type glutaminase.,Ramachandran S, Pan CQ, Zimmermann SC, Duvall B, Tsukamoto T, Low BC, Sivaraman J Oncotarget. 2016 Sep 6;7(36):57943-57954. doi: 10.18632/oncotarget.10791. PMID:27462863[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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