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腺苷蛋氨酸反应性胱硫醚β合酶调节 中的硫代谢和氧化还原平衡。

-Adenosylmethionine-responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in .

机构信息

Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka 560012, India.

Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka 560012, India.

出版信息

Sci Adv. 2022 Jun 24;8(25):eabo0097. doi: 10.1126/sciadv.abo0097.

DOI:10.1126/sciadv.abo0097
PMID:35749503
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9232105/
Abstract

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

摘要

蛋氨酸和半胱氨酸代谢对于 () 的存活和发病机制很重要。转硫途径将蛋氨酸转化为半胱氨酸，代表了不同生物体中抗氧化和甲基化代谢之间的重要联系。我们使用生物化学和冷冻电子显微镜的组合，对转硫途径的第一个酶，胱硫醚 β-合酶 (Cbs) 在 () 中进行了表征。我们证明 Cbs 是一种不含血红素、含有吡哆醛-5'-磷酸的酶，被 -腺苷甲硫氨酸 (SAM) 别构激活。Cbs 在其天然和 SAM 结合构象下的原子模型揭示了一种独特的 SAM 依赖性别构激活模式。此外，SAM 通过空间位阻阻止蛋白酶体降解来稳定 Cbs，这对于支持 () 中的蛋氨酸和氧化还原代谢至关重要。Cbs 的基因缺失会降低 () 在体外、巨噬细胞内以及感染 HIV 的小鼠中对半胱氨酸过载的生存能力。因此，Cbs-SAM 轴构成了协调 () 中硫代谢的重要机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/648e/9232105/da2f9e828bd6/sciadv.abo0097-f7.jpg
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