Inosine-5´-monophosphate dehydrogenase (IMPDH) catalyzes the rate limiting step of de novo purine synthesis. Currently, it remains still largely unknown how this metabolic event is regulated in tumor cells. Here, we report that a deacetylase sirtuin 5 (SIRT5) may possess a regulatory effect on GMP anabolism by desuccinylating IMPDH1. We found that SIRT5 can directly interacts with IMPDH1 and promotes desuccinylation on the N terminal of IMPDH1, thereby leading to increased IMPDH enzymatic activity, enhanced purine biosynthesis and promoted cell proliferation. Consistently, down-regulation of SIRT5 expression results in decreased IMPDH1 activity and impaired tumor cell proliferation. Therefore, our results reveal that SIRT5-mediated IMPDH1 desuccinylation adapts purine metabolism for rapid cell growth, and could be a potential therapeutic target for tumor cell proliferation inhibition.

中文翻译：

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SIRT5 对肌苷-5'-单磷酸脱氢酶 1 的去琥珀酰化促进肿瘤细胞增殖。


肌苷-5'-单磷酸脱氢酶 （IMPDH） 催化从头嘌呤合成的限速步骤。目前，这种代谢事件如何在肿瘤细胞中受到调节仍然在很大程度上是未知的。在这里，我们报道了脱乙酰酶 sirtuin 5 （SIRT5） 可能通过去琥珀酰化 IMPDH1 对 GMP 合成代谢具有调节作用。我们发现 SIRT5 可以直接与 IMPDH1 相互作用并促进 IMPDH1 的 N 端去琥珀酰化，从而导致 IMPDH 酶活性增加，增强嘌呤生物合成并促进细胞增殖。一致地，SIRT5 表达的下调导致 IMPDH1 活性降低和肿瘤细胞增殖受损。因此，我们的结果表明，SIRT5 介导的 IMPDH1 去琥珀酰化使嘌呤代谢适应细胞快速生长，并可能成为肿瘤细胞增殖抑制的潜在治疗靶点。