Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase
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 fr...
| Main Authors: | , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/135563 |
| _version_ | 1826201702950240256 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Dawson, Christopher D |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:55:26Z |
| format | Article |
| id | mit-1721.1/135563 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:55:26Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1355632023-12-19T21:43:41Z Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase 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 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 Institute 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. 2021-10-27T20:24:02Z 2021-10-27T20:24:02Z 2021 2021-06-14T12:27:33Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135563 en 10.1016/j.chembiol.2021.03.001 Cell Chemical Biology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | 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 Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title | Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title_full | Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title_fullStr | Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title_full_unstemmed | Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title_short | Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase |
| title_sort | molecular basis of c s bond cleavage in the glycyl radical enzyme isethionate sulfite lyase |
| url | https://hdl.handle.net/1721.1/135563 |
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