Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase
Author(s)
Dawson, Christopher D; Irwin, Stephania M; Backman, Lindsey RF; Le, Chip; Wang, Jennifer X; Vennelakanti, Vyshnavi; Yang, Zhongyue; Kulik, Heather J; Drennan, Catherine L; Balskus, Emily P; ... Show more Show less
DownloadPublished version (4.316Mb)
Publisher with Creative Commons License
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
Desulfonation of isethionate by the bacterial glycyl radical enzyme (GRE) isethionate sulfite-lyase (IslA) generates sulfite, a substrate for respiration that in turn produces the disease-associated metabolite hydrogen sulfide. Here, we present a 2.7 Å resolution X-ray structure of wild-type IslA from Bilophila wadsworthia with isethionate bound. In comparison with other GREs, alternate positioning of the active site β strands allows for distinct residue positions to contribute to substrate binding. These structural differences, combined with sequence variations, create a highly tailored active site for the binding of the negatively charged isethionate substrate. Through the kinetic analysis of 14 IslA variants and computational analyses, we probe the mechanism by which radical chemistry is used for C-S bond cleavage. This work further elucidates the structural basis of chemistry within the GRE superfamily and will inform structure-based inhibitor design of IsIA and thus of microbial hydrogen sulfide production.
Date issued
2021Department
Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Department of Chemical Engineering; Howard Hughes Medical InstituteJournal
Cell Chemical Biology
Publisher
Elsevier BV