S-Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance inMycobacteriumtuberculosis

Methionine and cysteine metabolisms are important for the survival and pathogenesis ofMycobacterium 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) inMtb. We demonstrated thatMtbCbs is a heme-less, pyridoxal-5′-phosphate–containing enzyme, allosterically activated byS-adenosylmethionine (SAM). The atomic model ofMtbCbs in its native and SAM-bound conformations revealed a unique mode of SAM-dependent allosteric activation. Further, SAM stabilizedMtbCbs by sterically occluding proteasomal degradation, which was crucial for supporting methionine and redox metabolism inMtb. Genetic deficiency ofMtbCbs reducedMtbsurvival upon homocysteine overload in vitro, inside macrophages, and in mice coinfected with HIV. Thus, theMtbCbs-SAM axis constitutes an important mechanism of coordinating sulfur metabolism inMtb.