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首页> 外文期刊>Nature >Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
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Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

机译：血红素加氧酶与肿瘤抑制因子富马酸酯水合酶合成杀伤力

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摘要

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)~1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions~(2-4). However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh J-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables FAl-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render FAl-deficient cells non-viable, while sparing wild-type Fh I-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fhl-deficien t cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fhl deficiency, providing a new potential target for treating HLRCC patients.
机译：富马酸盐水合酶（FH）是三羧酸循环（TCA循环）的酶，可催化富马酸盐水合成苹果酸。 FH的种系突变导致遗传性平滑肌瘤病和肾细胞癌（HLRCC）〜1。先前已经证明，缺乏FH会导致富马酸盐的积累，在正常的氧气压力下（2-4），富马酸盐会激活缺氧诱导因子（HIFs）。然而，到目前为止，还没有提供解释细胞在没有功能性TCA循环的情况下存活的机制。在这里，我们使用已删除Fh1的新鉴定的转基因肾脏小鼠细胞，并应用新开发的这些细胞的代谢计算机模型来预测和实验验证线性代谢途径，该途径从谷氨酰胺摄取开始，到从Fh排出胆红素结束J缺陷细胞。该途径涉及血红素的生物合成和降解，使FA1缺陷型细胞能够利用积累的TCA循环代谢物，并允许部分线粒体NADH的产生。我们预测并证实靶向该途径将使FA1缺陷的细胞不存活，同时保留野生型含Fh I的细胞。这项工作超出了鉴定在Fhl缺陷型t细胞中诱导的代谢途径的范围，从而证明了与Fhl缺乏症结合使用时对血红素氧合的抑制是致命的，为治疗HLRCC患者提供了新的潜在靶点。

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  • 来源
    《Nature》 |2011年第7363期|p.225-228|共4页
  • 作者

    Christian Frezza; Liang Zheng; Ori Folger; Kartik N. Rajagopalan; Elaine D. MacKenzie; Livnat Jerby; Massimo Micaroni; Barbara Chaneton; Julie Adam; Ann Hedley; Gabriela Kalna; Ian P. M. Tomlinson; Patrick J. Pollard; Dave G. Watson; Ralph J. Deberardinis; Tomer Shlomi; Eytan Ruppin; Eyal Gottlieb;

  • 作者单位

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    TheBlavatnikSchool of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel;

    Department of Pediatrics and McDermott Center for Human Growth and Development, University of Texas-Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9063, USA;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    heBlavatnikSchool of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel;

    Strathclyde Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, GlasgowG40NR, UK;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford 0X3 7BN, UK;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

    Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford 0X3 7BN, UK;

    Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford 0X3 7BN, UK;

    Strathclyde Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, GlasgowG40NR, UK;

    Department of Pediatrics and McDermott Center for Human Growth and Development, University of Texas-Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9063, USA;

    Computer Science Department, Technion, Israel Institute of Technology, Haifa, 32000, Israel;

    TheBlavatnikSchool of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel TheSackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;

    Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK;

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