Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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Title
Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor designAuthor (s)
Date
2020Publisher
Royal Society of ChemistryISSN
2041-6520; 2041-6539Bibliographic citation
REN, Weiwu, et al. Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design. Chemical Science, 2020, vol. 11, no 38, p. 10488-10495.Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/publishedVersionSubject
Abstract
Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors ... [+]
Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors of glycoside hydrolases (GHs) and as therapeutic leads in several disease areas. However, it is unclear how the carbasugars are recognized and processed by GHs. Here, we report the synthesis of three carbasugar isotopologues and provide a detailed transition state (TS) analysis for the formation of the initial GH-carbasugar covalent intermediate, as well as for hydrolysis of this intermediate, using a combination of experimentally measured kinetic isotope effects and hybrid QM/MM calculations. We find that the α-galactosidase from Thermotoga maritima effectively stabilizes TS charge development on a remote C5-allylic center acting in concert with the reacting carbasugar, and catalysis proceeds via an exploded, or loose, SN2 transition state with no discrete enzyme-bound cationic intermediate. We conclude that, in complement to what we know about the TS structures of enzyme-natural substrate complexes, knowledge of the TS structures of enzymes reacting with non-natural carbasugar substrates shows that GHs can stabilize a wider range of positively charged TS structures than previously thought. Furthermore, this enhanced understanding will enable the design of new carbasugar GH transition state analogues to be used as, for example, chemical biology tools and pharmaceutical lead compounds. [-]
Is part of
Chemical Science, 2020, vol. 11, no 38Investigation project
Natural Sciences and Engineering Research Council of Canada: RB 2019-06368, AJB 2017-04910; Spanish Ministerio de Ciencia, Innovacion y Universidades: PGC2018-094852-B-C21, PID2019-107098RJ-I00; Generalitat Valenciana: AICO/2019/195, SEJI/2020/007; Universitat Jaume I: UJI-B2017-31, UJI-A2019-04; MSFHR Career Investigator Award; MINECO: IJCI-2016-27503Rights
info:eu-repo/semantics/openAccess
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