Journal of Medicinal Chemistry p. 3286 - 3296 (2019)
Update date:2022-08-16
Topics:
Harijan, Rajesh K.
Hoff, Oskar
Ducati, Rodrigo G.
Firestone, Ross S.
Hirsch, Brett M.
Evans, Gary B.
Schramm, Vern L.
Tyler, Peter C.
Bacterial 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5′-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5′-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5′-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.
View MoreChengdu D-Innovation Pharmaceutical Co., Ltd
Contact:86-28-85105536
Address:1001, B6, No.88 Keyuan South Road, Chengdu Hi-Tech Zone
Shenzhen JYMed Technology Co.,Ltd.
website:http://www.jymedtech.com
Contact:+86-755-26612112
Address:RM1-105, Shenzhen Bio-incubator Base, 10 Gaoxin C Avc 1st, Nanshan District, Shenzhen, GD, China, 518057
Tianjin Boron PharmaTech Co.,Ltd.
Contact:86-022-59845187
Address:B9-401, Tianda Science Park,No.80,4th Avenue,TEDA,Tianjin, China
Contact:+36(21)2523420
Address:Head office: 1102 Budapest, SZENT LASZLO TER 24/B. 1/1., HUNGARY / CHINA
website:https://www.bocsci.com/
Contact:1-631-485-4226
Address:Ramsey Road
Doi:10.1021/jo300598d
(2012)Doi:10.1016/j.chemphys.2016.03.010
(2016)Doi:10.1021/jm00097a016
(1992)Doi:10.1021/ja01104a032
(1953)Doi:10.1039/c5ra07171b
(2015)Doi:10.1021/op8001678
(2008)