Biology:Isethionate sulfite-lyase
Isethionate sulfite-lyase (IslA, IseA or IseG) is a glycyl radical enzyme that catalyzes the degradation of isethionate into acetaldehyde and sulfite through the cleavage of a carbon-sulfur bond.[1] This conversion is a necessary step for taurine catabolism in anaerobic bacteria like Bilophila wadsworthia. IslA is activated by the enzyme IslB which uses S-adenoslymethionine (SAM) as the initial radical donor.
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Structure
IslA, like all other characterized glycyl radical enzymes, is a dimeric protein. The IslA monomer contains a barrel made of alpha helices that envelop two five-stranded half-beta barrels positioned antiparallel to each other.[2] Hidden within this barrel is the active site of the enzyme. It is believed that the positioning of the active site within the barrel protects the radical species (formed during the activation of the enzyme) from solvent quenching.[3]
Function
Enzyme activation
Activation of IslA depends on binding of glycyl radical enyzme-activating enzyme IslB, which catalyzes the initial formation of the radical S-adenosylmethionine (rSAM) species. rSAM is formed by the one-electron reduction of an iron-sulfur cluster, and the resulting radical is stabilized by amino acid residues within the enzyme.[4] The formation of the stable complex between the two enzymes and the binding of glycine in the active site of IslB are prerequisites for successful activation of IslA.[4]
Mechanism of action
The radical-based cleavage of IslA is thought to occur through a direct elimination reaction.[2] However, recent research indicates that a 1,2-SO3-radical migration may occur after a catalytically active cysteine residue radical grabs a hydrogen atom from isethionate, followed by hydrogen atom transfer from cysteine to a 1-hydroxylethane-1-sulfonate radical intermediate.[5] The elimination of sulfite from 1-hydroxylethane-1-sulfonate to result in the final product is likely to occur outside the enzyme.[5] This mechanism is similar to the reported fragmentation-recombination mechanism of B12-dependent glutamate mutase.[5]
Evolution of structure
Radicals are very chemically unstable species and must be carefully controlled in biological systems. Research supports the theory that GREs converged on glycyl radical formation due to the better conformational accessibility of the glycine radical loop, rather than the highest radical stability of the formed peptide radicals.[6]
Physiological role
Disease
Isla produced by Bilophila wadsworthia is known to convert organosulfides including taurine and isethionate into acetaldehyde and sulfite. Sulfite is converted into hydrogen sulfide, which can degrade the mucous lining of the colon and cause pathological conditions including colorectal cancer, inflammatory bowel diseases, and colitis.[3] Moreover, hydrogen sulfide has been known to induce antibiotic resistance suggesting that the production of this molecule could prompt blooms of opportunistic bacteria during antibiotic treatment.[7] Conversely, hydrogen sulfide may also act as a signaling molecule within the homeostasis of a host's circulatory system such as regulating blood pressure control.[8] Ultimately, although the role of hydrogen sulfide within disease may be unclear, efforts to find inhibitors for IslA may help mitigate the excess production of hydrogen sulfide.
Bacterial microcompartments
Within the same gene cluster that encodes IslA and IslB enzymes are several genes that encode shell proteins of bacterial microcompartments (BMCs). It has been found that the IslA and IslB enzymes are likely contained within BMCs which isolate the products of IslA (acetaldehyde and sulfite) from the cytosol and limits their harmful effects.[9] Flavin molecules, which are also present in the BMCs, may be used to shuttle electrons to the IslB enzyme which is necessary to install the glycyl radical on the IslA enzyme upon activation.
Industrial relevance
Anaerobic radical enzymes such as IslA have the potential to functionally modify a substrate without oxygen incorporation, requiring less expensive adaptation of downstream synthetic methodologies than from oxygen-rich biomass-derived feedstocks.[10] The ability to catabolize amino acids to generate a broad range of branched and unbranched hydrocarbon chains could be useful in production of biofuels. In addition, radical catalysis enables a range of specialist reactions of industrial interest, including carbon-skeleton rearrangements, aminomutases, and eliminases.[10]
References
- ↑ "A glycyl radical enzyme enables hydrogen sulfide production by the human intestinal bacterium Bilophila wadsworthia". Proceedings of the National Academy of Sciences of the United States of America 116 (8): 3171–3176. February 2019. doi:10.1073/pnas.1815661116. PMID 30718429. Bibcode: 2019PNAS..116.3171P.
- ↑ 2.0 2.1 "Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase" (in English). Cell Chemical Biology 28 (9): 1333–1346.e7. September 2021. doi:10.1016/j.chembiol.2021.03.001. PMID 33773110.
- ↑ 3.0 3.1 "Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase (Isla) from Bilophila wadsworthia: Combating Colorectal Cancer and Inflammatory Bowel Diseases". Cancers 15 (3): 901. January 2023. doi:10.3390/cancers15030901. PMID 36765864.
- ↑ 4.0 4.1 "Structure–function relationships of radical SAM enzymes" (in en). Nature Catalysis 3 (4): 337–350. 13 April 2020. doi:10.1038/s41929-020-0448-7. ISSN 2520-1158.
- ↑ 5.0 5.1 5.2 "Revealing the Mechanism of Isethionate Sulfite-Lyase by QM/MM Calculations". Journal of Chemical Information and Modeling 61 (12): 5871–5882. December 2021. doi:10.1021/acs.jcim.1c00978. PMID 34806370.
- ↑ "Activation of Glycyl Radical Enzymes─Multiscale Modeling Insights into Catalysis and Radical Control in a Pyruvate Formate-Lyase-Activating Enzyme". Journal of Chemical Information and Modeling 62 (14): 3401–3414. July 2022. doi:10.1021/acs.jcim.2c00362. PMID 35771966.
- ↑ "H2S: a universal defense against antibiotics in bacteria". Science 334 (6058): 986–990. November 2011. doi:10.1126/science.1209855. PMID 22096201. Bibcode: 2011Sci...334..986S.
- ↑ "Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis". Molecules 21 (11): 1558. November 2016. doi:10.3390/molecules21111558. PMID 27869680.
- ↑ "Bacterial microcompartments for isethionate desulfonation in the taurine-degrading human-gut bacterium Bilophila wadsworthia". BMC Microbiology 21 (1): 340. December 2021. doi:10.1186/s12866-021-02386-w. PMID 34903181.
- ↑ 10.0 10.1 "Anaerobic Radical Enzymes for Biotechnology" (in en). ChemBioEng Reviews 5 (3): 143–162. Jun 30, 2018. doi:10.1002/cben.201800003. https://onlinelibrary.wiley.com/doi/10.1002/cben.201800003.
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