D2HGDH 通过调节 IDH2 调节 α-酮戊二酸水平和双加氧酶功能。,Nature Communications

当前位置： X-MOL 学术 › Nat. Commun. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

D2HGDH 通过调节 IDH2 调节 α-酮戊二酸水平和双加氧酶功能。
Nature Communications ( IF 14.7 ) Pub Date : 2015-Jul-16 , DOI: 10.1038/ncomms8768
An-Ping Lin ₁ , Saman Abbas ₁ , Sang-Woo Kim ₁ , Manoela Ortega ₁ , Hakim Bouamar ₁ , Yissela Escobedo ₁ , Prakash Varadarajan ₁ , Yuejuan Qin ₁ , Jessica Sudderth ₂ , Eduard Schulz ₃ , Alexander Deutsch ₃ , Sumitra Mohan ₄ , Peter Ulz ₄ , Peter Neumeister ₃ , Dinesh Rakheja ₅ , Xiaoli Gao ₆ , Andrew Hinck ₆ , Susan T Weintraub ₆ , Ralph J DeBerardinis ₂ , Heinz Sill ₃ , Patricia L M Dahia ₇ , Ricardo C T Aguiar ₈

Affiliation

Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA.
Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
1] Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA [2] Department of Pathology and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [4] South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas 78229, USA.

异柠檬酸脱氢酶 (IDH) 将异柠檬酸转化为 α-酮戊二酸 (α-KG)。在癌症中，突变 IDH1/2 将 α-KG 还原为 D2-羟基戊二酸 (D2-HG)，从而破坏 α-KG 依赖性双加氧酶。然而，控制由 D2-羟基戊二酸脱氢酶 (D2HGDH) 介导的 D2-HG 相互转化为 α-KG 的生理相关性仍然不清楚。在这里，我们显示野生型 D2HGDH 提高 α-KG 水平，影响组蛋白和 DNA 甲基化，以及 HIF1α 羟基化。相反，我们在弥漫性大 B 细胞淋巴瘤中发现的 D2HGDH 突变体是酶惰性的。D2-HG 是一种低丰度代谢物，但我们表明它可以通过正向调节线粒体 IDH 活性和诱导 IDH2 表达来显着提高 α-KG 水平。因此，IDH2 的基因缺失消除了 D2HGDH 效应，而异位 IDH2 拯救 D2HGDH 缺陷细胞。我们的数据将 D2HGDH 与癌症联系起来，并描述了该酶的另一个作用：调节 IDH2 活性和 α-KG 介导的表观遗传重塑。这些数据进一步揭示了线粒体代谢的复杂性，并为 D2HGDH 缺陷疾病的发病机制提供了信息。

"点击查看英文标题和摘要"

更新日期：2015-07-18

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南