What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

被引：467

作者：

Losman, Julie-Aurore ^{[1
]}

Kaelin, William G., Jr. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Med Oncol, Boston, MA 02215 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

GENES & DEVELOPMENT | 2013年 / 27卷 / 08期

关键词：

2-oxoglutarate-dependent dioxygenase; cancer metabolism; chondrosarcoma; glioma; isocitrate dehydrogenase; leukemia; ACUTE MYELOID-LEUKEMIA; NADP(+)-DEPENDENT ISOCITRATE DEHYDROGENASE; CELL SELF-RENEWAL; HEMATOPOIETIC STEM-CELLS; TRICARBOXYLIC-ACID CYCLE; TET2; MUTATIONS; D-2-HYDROXYGLUTARIC ACIDURIA; MYELODYSPLASTIC SYNDROMES; TCA CYCLE; IN-VIVO;

D O I：

10.1101/gad.217406.113

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.

引用

页码：836 / 852

页数：17

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