EMD-33348
Cryo-EM map of cystathionine beta-synthase of Mycobacterium tuberculosis in the presence of S-adenosylmethionine.
EMD-33348
Single-particle3.6 Å
Deposition: 01/05/2022Map released: 25/05/2022
Last modified: 07/12/2022
Sample Organism:
Mycobacterium tuberculosis H37Rv
Sample: Cystathionine beta-synthase of Mycobacterium tuberculosis in the presence of S-adenosylmethionine.
Fitted models: 7xoh (Avg. Q-score: 0.502)
Deposition Authors: Bandyopadhyay P
,
Pramanick I ,
Biswas R,
Sabarinath PS,
Sreedharan S,
Singh S ,
Rajmani R,
Laxman S ,
Dutta S ,
Singh A
Sample: Cystathionine beta-synthase of Mycobacterium tuberculosis in the presence of S-adenosylmethionine.
Fitted models: 7xoh (Avg. Q-score: 0.502)
Deposition Authors: Bandyopadhyay P
,
Pramanick I ,
Biswas R,
Sabarinath PS,
Sreedharan S,
Singh S ,
Rajmani R,
Laxman S ,
Dutta S ,
Singh A
S-Adenosylmethionine-responsive cystathionine beta-synthase modulates sulfur metabolism and redox balance in Mycobacterium tuberculosis.
Bandyopadhyay P ,
Pramanick I ,
Biswas R,
Ps S ,
Sreedharan S,
Singh S ,
Rajmani RS,
Laxman S ,
Dutta S ,
Singh A
(2022) Sci Adv , 8 , eabo0097 - eabo0097
,
Pramanick I ,
Biswas R,
Ps S ,
Sreedharan S,
Singh S ,
Rajmani RS,
Laxman S ,
Dutta S ,
Singh A
(2022) Sci Adv , 8 , eabo0097 - eabo0097
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.
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.