<i>S</i> -Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in <i>Mycobacterium</i> <i>tuberculosis</i>
Parijat Bandyopadhyay, Ishika Pramanick, Rupam Biswas, Sabarinath PS, Sreesa Sreedharan, Shalini Singh, Raju S Rajmani, Sunil Laxman, Somnath Dutta, Amit Singh
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 ( Mtb Cbs) in Mtb . We demonstrated that Mtb Cbs is a heme-less, pyridoxal-5′-phosphate–containing enzyme, allosterically activated by S -adenosylmethionine (SAM). The atomic model of Mtb Cbs in its native and SAM-bound conformations revealed a unique mode of SAM-dependent allosteric activation. Further, SAM stabilized Mtb Cbs by sterically occluding proteasomal degradation, which was crucial for supporting methionine and redox metabolism in Mtb . Genetic deficiency of Mtb Cbs reduced Mtb survival upon homocysteine overload in vitro, inside macrophages, and in mice coinfected with HIV. Thus, the Mtb Cbs-SAM axis constitutes an important mechanism of coordinating sulfur metabolism in Mtb .