A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis
Abstract Methionine is essential for the growth and survival of Mycobacterium tuberculosis (M. tuberculosis), however, the canonical transsulfuration pathway involved in the biosynthesis of methionine is dispensable, suggesting redundancy. This study explores the presence of an ortholog of O-succiny...
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08051-6 |
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| author | Vaibhav Kumar Nain Vishawjeet Barik Manitosh Pandey Mohit Pareek Taruna Sharma Rahul Pal Shaifali Tyagi Manish Bajpai Prabhanjan Dwivedi Bhishma Narayan Panda Yashwant Kumar Shailendra Asthana Amit Kumar Pandey |
| author_facet | Vaibhav Kumar Nain Vishawjeet Barik Manitosh Pandey Mohit Pareek Taruna Sharma Rahul Pal Shaifali Tyagi Manish Bajpai Prabhanjan Dwivedi Bhishma Narayan Panda Yashwant Kumar Shailendra Asthana Amit Kumar Pandey |
| author_sort | Vaibhav Kumar Nain |
| collection | DOAJ |
| description | Abstract Methionine is essential for the growth and survival of Mycobacterium tuberculosis (M. tuberculosis), however, the canonical transsulfuration pathway involved in the biosynthesis of methionine is dispensable, suggesting redundancy. This study explores the presence of an ortholog of O-succinyl homoserine sulfhydrylase in M. tuberculosis, which catalyses direct sulfhydrylation for methionine biosynthesis. Bioinformatics analysis of putative O-succinyl homoserine sulfhydrylase encoded by metZ in M. tuberculosis showed similarities with its orthologues in other bacterial species. Here, we show that metZ deletion in M. tuberculosis resulted in impaired growth under acidic conditions, which was reversed by methionine supplementation. Molecular dynamics simulation studies revealed improved binding of substrate, O-succinyl homoserine, to the active site of MetZ at low pH mimicking the phagosomal microenvironment. Intriguingly, despite higher ATP levels, metZ deletion reduced the frequency of Bedaquiline-induced persister formation. Finally, we demonstrate that loss of metZ hinders M. tuberculosis growth inside the host. |
| format | Article |
| id | doaj-art-3772a4de0fa24463b2b94add85759d16 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-3772a4de0fa24463b2b94add85759d162025-08-20T02:28:10ZengNature PortfolioCommunications Biology2399-36422025-04-018111510.1038/s42003-025-08051-6A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosisVaibhav Kumar Nain0Vishawjeet Barik1Manitosh Pandey2Mohit Pareek3Taruna Sharma4Rahul Pal5Shaifali Tyagi6Manish Bajpai7Prabhanjan Dwivedi8Bhishma Narayan Panda9Yashwant Kumar10Shailendra Asthana11Amit Kumar Pandey12Mycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteComputational Biophysics and CADD Group, Computational and Mathematical Biology Centre, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteBiomarker Discovery Laboratory, Centre for Drug Discovery, BRIC-Translational Health Science and Technology InstituteExperimental Animal Facility, BRIC-Translational Health Science and Technology InstituteExperimental Animal Facility, BRIC-Translational Health Science and Technology InstituteBiomarker Discovery Laboratory, Centre for Drug Discovery, BRIC-Translational Health Science and Technology InstituteComputational Biophysics and CADD Group, Computational and Mathematical Biology Centre, BRIC-Translational Health Science and Technology InstituteMycobacterial Pathogenesis Laboratory, Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology InstituteAbstract Methionine is essential for the growth and survival of Mycobacterium tuberculosis (M. tuberculosis), however, the canonical transsulfuration pathway involved in the biosynthesis of methionine is dispensable, suggesting redundancy. This study explores the presence of an ortholog of O-succinyl homoserine sulfhydrylase in M. tuberculosis, which catalyses direct sulfhydrylation for methionine biosynthesis. Bioinformatics analysis of putative O-succinyl homoserine sulfhydrylase encoded by metZ in M. tuberculosis showed similarities with its orthologues in other bacterial species. Here, we show that metZ deletion in M. tuberculosis resulted in impaired growth under acidic conditions, which was reversed by methionine supplementation. Molecular dynamics simulation studies revealed improved binding of substrate, O-succinyl homoserine, to the active site of MetZ at low pH mimicking the phagosomal microenvironment. Intriguingly, despite higher ATP levels, metZ deletion reduced the frequency of Bedaquiline-induced persister formation. Finally, we demonstrate that loss of metZ hinders M. tuberculosis growth inside the host.https://doi.org/10.1038/s42003-025-08051-6 |
| spellingShingle | Vaibhav Kumar Nain Vishawjeet Barik Manitosh Pandey Mohit Pareek Taruna Sharma Rahul Pal Shaifali Tyagi Manish Bajpai Prabhanjan Dwivedi Bhishma Narayan Panda Yashwant Kumar Shailendra Asthana Amit Kumar Pandey A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis Communications Biology |
| title | A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis |
| title_full | A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis |
| title_fullStr | A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis |
| title_full_unstemmed | A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis |
| title_short | A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis |
| title_sort | ph dependent direct sulfhydrylation pathway is required for the pathogenesis of mycobacterium tuberculosis |
| url | https://doi.org/10.1038/s42003-025-08051-6 |
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