S-Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in Mycobacterium tuberculosis

Parijat Bandyopadhyay, Ishika Pramanick, Rupam Biswas, P. S. Sabarinath, Sreesa Sreedharan, Shalini Singh, Raju S. Rajmani, Sunil Laxman, Somnath Dutta, Amit Singh

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9 Scopus citations


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.

Original languageEnglish (US)
Article numbereabo0097
JournalScience Advances
Issue number25
StatePublished - Jun 2022
Externally publishedYes

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