Redox-switch modulation of human SSADH by dynamic catalytic loop
Redox-switch modulation of human SSADH by dynamic catalytic loop
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DOI：
10.1038/emboj.2009.40
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发表时间：
2009-04-08
期刊：
影响因子：
11.4
通讯作者：
Kim, Kyung-Jin
中科院分区：
文献类型：
--
作者：
Kim, Yeon-Gil;Lee, Sujin;Kim, Kyung-Jin
琥珀酸半醛脱氢酶通过将线粒体基质中的琥珀酸半醛转化为琥珀酸，参与抑制性神经递质γ-氨基丁酸的最终降解。SSADH缺乏症是一种罕见的常染色体隐性遗传病，临床表现多样，包括精神运动发育迟缓、语言迟缓、行为障碍和惊厥。在这里，我们介绍了氧化和还原形式的人SSADH的晶体结构。有趣的是，结构表明，酶的催化环根据环境的氧化还原状态经历了很大的结构变化，这是由位于环上的催化Cys340和相邻的Cys342残基之间形成的可逆二硫键所介导的。随后的体内和体外研究表明，动态催化环对活性氧物种和氧化还原状态的变化做出反应，表明氧化还原开关调节可能是人类SSADH的一种生理调控机制。还介绍了该酶底物特异性的结构基础以及与疾病发病机制相关的已知错义点突变的影响。
Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SSADH deficiency, a rare autosomal recessive disease, exhibits variable clinical phenotypes, including psychomotor retardation, language delay, behaviour disturbance and convulsions. Here, we present crystal structures of both the oxidized and reduced forms of human SSADH. Interestingly, the structures show that the catalytic loop of the enzyme undergoes large structural changes depending on the redox status of the environment, which is mediated by a reversible disulphide bond formation between a catalytic Cys340 and an adjacent Cys342 residues located on the loop. Subsequent in vivo and in vitro studies reveal that the 'dynamic catalytic loop' confers a response to reactive oxygen species and changes in redox status, indicating that the redox-switch modulation could be a physiological control mechanism of human SSADH. Structural basis for the substrate specificity of the enzyme and the impact of known missense point mutations associated with the disease pathogenesis are presented as well.