Bandyopadhyay, P and Pramanick, I and Biswas, R and Sabarinath, PS and Sreedharan, S and Singh, S and Rajmani, RS and Laxman, S and Dutta, S and Singh, A (2022) S-Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in Mycobacterium tuberculosis. In: Science Advances, 8 (25).
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Abstract
Methionine and cysteine metabolisms are important for the survival and pathogenesis of Mycobacterium tuberculosis (Mtb). The transsulfuration pathway converts methionine to cysteine and represents an important link between antioxidant and methylation metabolism in diverse organisms. Using a combination of biochemistry and cryo–electron microscopy, we characterized the first enzyme of the transsulfuration pathway, cystathionine β-synthase (MtbCbs) in Mtb. We demonstrated that MtbCbs is a heme-less, pyridoxal-5′-phosphate–containing enzyme, allosterically activated by S-adenosylmethionine (SAM). The atomic model of MtbCbs in its native and SAM-bound conformations revealed a unique mode of SAM-dependent allosteric activation. Further, SAM stabilized MtbCbs by sterically occluding proteasomal degradation, which was crucial for supporting methionine and redox metabolism in Mtb. Genetic deficiency of MtbCbs reduced Mtb survival upon homocysteine overload in vitro, inside macrophages, and in mice coinfected with HIV. Thus, the MtbCbs-SAM axis constitutes an important mechanism of coordinating sulfur metabolism in Mtb.
| Item Type: | Journal Article |
|---|---|
| Publication: | Science Advances |
| Publisher: | American Association for the Advancement of Science |
| Additional Information: | The copyright for this article belongs to the Author(s). |
| Keywords: | Alkylation; Amino acids; Enzymes; Mammals; Methylation; Sulfur, Allosteric activation; Atomic models; Cryo-electron microscopy; Diverse organisms; Methionine; Mycobacterium tuberculosis; Pyridoxal 5�-phosphate; Redox balances; S-adenosylmethionine; Synthases, Metabolism, ademetionine; cystathionine beta synthase; cysteine; methionine; pyridoxal 5 phosphate; sulfur, animal; chemistry; cryoelectron microscopy; genetics; metabolism; mouse; Mycobacterium tuberculosis; oxidation reduction reaction, Animals; Cryoelectron Microscopy; Cystathionine beta-Synthase; Cysteine; Methionine; Mice; Mycobacterium tuberculosis; Oxidation-Reduction; Pyridoxal Phosphate; S-Adenosylmethionine; Sulfur |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research |
| Date Deposited: | 19 Sep 2022 05:18 |
| Last Modified: | 19 Sep 2022 05:18 |
| URI: | https://eprints.iisc.ac.in/id/eprint/76539 |
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