<i>S</i>-Adenosylmethionine-responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in <i>Mycobacterium</i> <i>tuberculosis</i>.

Abstract

Methionine and cysteine metabolisms are important for the survival and pathogenesis of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). 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 (<i>Mtb</i>Cbs) in <i>Mtb</i>. We demonstrated that <i>Mtb</i>Cbs is a heme-less, pyridoxal-5'-phosphate-containing enzyme, allosterically activated by <i>S</i>-adenosylmethionine (SAM). The atomic model of <i>Mtb</i>Cbs in its native and SAM-bound conformations revealed a unique mode of SAM-dependent allosteric activation. Further, SAM stabilized <i>Mtb</i>Cbs by sterically occluding proteasomal degradation, which was crucial for supporting methionine and redox metabolism in <i>Mtb</i>. Genetic deficiency of <i>Mtb</i>Cbs reduced <i>Mtb</i> survival upon homocysteine overload in vitro, inside macrophages, and in mice coinfected with HIV. Thus, the <i>Mtb</i>Cbs-SAM axis constitutes an important mechanism of coordinating sulfur metabolism in <i>Mtb</i>.