Abstract
SummaryDesulfonation 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.
Highlights
Certain gut bacteria release hydrogen sulfide as a byproduct of their respiration, which has implications for human health
Overall architecture of isethionate sulfite-lyase (IslA) is consistent with other glycyl radical enzyme (GRE) eliminases A structure of IslA from B. wadsworthia 3.1.6 was solved to 2.26 Aresolution by molecular replacement using CutC (PDB: 5FAU; Bodea et al, 2016) as the search model (Table 1) with
The structure of WT IsIA from B. wadsworthia with Ise bound has allowed us to compare how this GRE binds substrate with how other GRE eliminases position their substrates for catalysis
Summary
Certain gut bacteria release hydrogen sulfide as a byproduct of their respiration, which has implications for human health. Increased levels of hydrogen sulfide-producing bacteria are linked to a thinner colonic mucus barrier and multiple diseases, including inflammatory bowel disease (Ijssennagger et al, 2016), Crohn’s disease, ulcerative colitis (Carbonero et al, 2012; Singh and Lin, 2015), and colorectal cancer (Yazici et al, 2017). Hydrogen sulfide levels in the human body depend largely on the gut microbiome (Shen et al, 2013) and have been implicated in circulatory system homeostasis (Tomasova et al, 2016) and antibiotic neutralization (Shatalin et al, 2011). Targeting hydrogen sulfide production by B. wadsworthia and other gut bacteria, such as sulfate-reducing bacteria (SRB), could become a therapeutic strategy to address these medical issues
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