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SIRT5介导的5'-肌苷单磷酸脱氢酶1去琥珀酰化促进肿瘤细胞增殖。

Desuccinylation of inosine-5'-monophosphate dehydrogenase 1 by SIRT5 promotes tumor cell proliferation.

作者信息

Xu Chang, Yao Pengbo, Cheng Jie, Jiang Peng

机构信息

Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China; Department of Pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.

出版信息

J Biol Chem. 2024 Dec;300(12):107976. doi: 10.1016/j.jbc.2024.107976. Epub 2024 Nov 8.

DOI:10.1016/j.jbc.2024.107976
PMID:39522945
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11647618/
Abstract

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 interact 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, downregulation 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.

摘要

肌苷-5'-单磷酸脱氢酶（IMPDH）催化嘌呤从头合成的限速步骤。目前，肿瘤细胞中这种代谢事件是如何被调控的在很大程度上仍然未知。在此，我们报告一种去乙酰化酶沉默调节蛋白5（SIRT5）可能通过使IMPDH1去琥珀酰化而对鸟苷酸合成代谢具有调节作用。我们发现SIRT5能直接与IMPDH1相互作用，并促进IMPDH1 N端的去琥珀酰化，从而导致IMPDH酶活性增加、嘌呤生物合成增强及细胞增殖促进。一致地，SIRT5表达下调导致IMPDH1活性降低及肿瘤细胞增殖受损。因此，我们的结果揭示SIRT5介导的IMPDH1去琥珀酰化使嘌呤代谢适应细胞快速生长，并且可能是抑制肿瘤细胞增殖的一个潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/211c31505ff6/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/fd40b5b437f6/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/bfb81778d8aa/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/3cbc372694ab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/211c31505ff6/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/fd40b5b437f6/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/bfb81778d8aa/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/3cbc372694ab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e64/11647618/211c31505ff6/gr4.jpg

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Cell Death Differ. 2024 Jan;31(1):65-77. doi: 10.1038/s41418-023-01240-y. Epub 2023 Nov 25.
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Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability.
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Cancer Res. 2018 Jan 15;78(2):372-386. doi: 10.1158/0008-5472.CAN-17-1912. Epub 2017 Nov 27.
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The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes.细胞体及其同类：代谢酶的丝状化和区室化。
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