Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase
| Autor: | Stephania M. Irwin, Christopher D. Dawson, Jennifer X. Wang, Heather J. Kulik, Emily P. Balskus, Vyshnavi Vennelakanti, Chip Le, Catherine L. Drennan, Zhongyue Yang, Lindsey R. F. Backman |
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| Rok vydání: | 2021 |
| Předmět: |
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Molecular Stereochemistry lyase Radical Clinical Biochemistry hydrogen sulfide Lyases Bilophila Biology Crystallography X-Ray 01 natural sciences Biochemistry Article Turn (biochemistry) Residue (chemistry) chemistry.chemical_compound sulfite Sulfite Drug Discovery Molecular Biology isethionate Bond cleavage carbon-sulfur bond cleavage Pharmacology human gut microbiome 010405 organic chemistry Bilophila wadsworthia structural enzymology Substrate (chemistry) Active site Lyase Carbon 0104 chemical sciences chemistry sulfate-reducing bacteria biology.protein Molecular Medicine glycyl radical enzyme Sulfur |
| Zdroj: | Cell Chemical Biology |
| ISSN: | 2451-9456 |
| Popis: | Summary 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. Graphical abstract Highlights • Molecular basis for sulfite production in the human gut • Crystallographic snapshots of a glycyl radical enzyme found in the human gut • Molecular mechanism of radical-based C-S bond cleavage investigated • Canonical glycyl radical enzyme β barrel is tailored to enable sulfonate binding Dawson, Irwin et al. provide a molecular depiction of how sulfite, a precursor to the cancer- and Crohn's disease-associated metabolite hydrogen sulfide, is generated from isethionate by the enzyme isethionate sulfite-lyase in the human gut microbiota. |
| Databáze: | OpenAIRE |
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