Department of Cell Biology, Peking University Health Science Center, 100191, Beijing, China.
Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, 100191, Beijing, China.
Biol Chem. 2020 Aug 27;401(9):1031-1039. doi: 10.1515/hsz-2020-0118.
Citrate synthase (CS), the rate-limiting enzyme in the tricarboxylic acid (TCA) cycle catalyzes the first step of the cycle, namely, the condensation of oxaloacetate and acetyl-CoA to produce citrate. The expression and enzymatic activity of CS are altered in cancers, but posttranslational modification (PTM) of CS and its regulation in tumorigenesis remain largely obscure. SIRT5 belongs to the nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase sirtuin family and plays vital roles in multiple biological processes via modulating various substrates. Here, we show that SIRT5 interacts with CS and that SIRT5 desuccinylates CS at the evolutionarily conserved residues K393 and K395. Moreover, hypersuccinylation of CS at K393 and K395 dramatically reduces its enzymatic activity and suppresses colon cancer cell proliferation and migration. These results provide experimental evidence in support of a potential therapeutic approach for colon cancer.
柠檬酸合酶（CS）是三羧酸（TCA）循环中的限速酶，催化该循环的第一步，即草酰乙酸和乙酰辅酶 A 的缩合生成柠檬酸。CS 的表达和酶活性在癌症中发生改变，但 CS 的翻译后修饰（PTM）及其在肿瘤发生中的调控仍很大程度上不清楚。SIRT5 属于烟酰胺腺嘌呤二核苷酸（NAD）+依赖性去乙酰化酶 sirtuin 家族，通过调节多种底物在多种生物学过程中发挥重要作用。在这里，我们表明 SIRT5 与 CS 相互作用，并且 SIRT5 在进化上保守的残基 K393 和 K395 上将 CS 去琥珀酰化。此外，CS 在 K393 和 K395 处的过度琥珀酰化显著降低其酶活性，并抑制结肠癌细胞增殖和迁移。这些结果为支持结肠癌的潜在治疗方法提供了实验依据。
