异柠檬酸脱氢酶(IDH)突变与癌症的关系

2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases.
……Three years later
Chalmers et al (1980) identified a patient with D-2-hydroxyglutaric aciduria (D-2HGA)
Duran et al (1980) described a case of L-2-hydroxyglutaric aciduria (L-2-HGA)
Losman et al., Gene& Development 27: 836-852, 2013
Lenny Dang et al. IDH mutations in glioma and acute myeloid leukemia. Trends in Molecular Medicine 16 (2010) 387–397
Isocitrate
dehydrogenase
(IDH)mutation and
cancer 异柠檬酸脱氢酶(IDH)突
变与癌症的ቤተ መጻሕፍቲ ባይዱ系
NAD+ NADH
The role of the IDH family of enzymes in the TCA cycle.
Summary of metabolic genes and the associated tumor types
Sasaki et al., Genes Dev 26: 2038-2049, 2012 Koivunen et al., Nature 483: 484-488, 2012
Histone demethylases
5mC hydroxylases
Collagen hydroxylase
PHD: HIF prolyl hydroxylase; vHL: von Hippel Lindau protein (E3); VEGF: vascular endothelial growth factor; SLC2A: solute carrier family 2 member 1
2-HG
a-ketoglutarate, a-KG 2-oxoglutarate
2-hydroxyglutaric aciduria (2-HGA)
Identification of enantiomeric D- and L-2hydroxyglutarate
Gregersen N, Ingerslev J, Rasmussen K (1977) Low molecular weight organic acids in the urine of the newborn. Acta Paediatr Scand 66:85–89 LC-MASS
IDH2 heterozygous muation
SLC25A1 Inactive mutation （citrate carrier）
overview of 2-HGA
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Combined D,L-2-hydroxyglutaric aciduria
How is 2-hdroxyglutarate produced?
Fatty acids biosynthesis
Materials: acetyl-CoA and NADPH Site: in the cytosol Acetyl-CoA is came from pyruvate, fatty acid oxidation of mitochondrial matrix, and glycogenic amino acid.
GIST: gastrointestinal stromal tumor; RCC: renal cell cancer
IDH mutations have also been found in paraganglioma, colon cancer, prostate cancer, and lung cancer (Sjoblom et al. 2006; Bleeker et al. 2009; Kang et al. 2009; Gaal et al. 2010; Sequist et al. 2011; Borger et al. 2012). 2°GBM: secondary glioblastoma multiforme; NK: normal karyotype，AITL: angioimmunoblastic T-cell lymphoma (血管免疫母细胞); cholangiocarcinoma
John R Prensner et al. Metabolism unhinged: IDH mutations in cancer. Nature Medicine, 17 (3): 291-293, 2011
2013 May 17
EGLN1 gene encodes prolyl hydroxylase domain-containing protein 2 (PHD2)/ EGLN1
In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC).
2-HG inhibits H3K9 demethylase KDM4C
Symptom and diagosis
neurological impairment at young age Unexplained developmental delay other neurological dysfunction of unknown etiology : seizures,
D-2HGA type Ⅰ
D-2-HGDH: D-2-hydroxyglutarate dehydrogenase enzyme
D2HGDH mutations: the molecular basis of D-2HGA typeⅠ
D-2-HGDH showed hight affinity for D-2-HG and is responsible for the convertion of D-2-HG to 2-KG using FAD as a cofactor. It was been documented that mutations cause the impairment in this enzyme reaction would result in D-2HGA.
lysyl-5-hydoxylase Prolyl-3-hydoxylase
AGI-5198 inhibits the formation of IDH1 R132H homo- and hetero-dimer
AGI-6780 potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface.
Muntau et al (2000) described a third biochemical variant of 2-hydroxyglutaric aciduria (2-HGA) ,“combined D,L-2 hydroxyglutaric aciduria”(D,L-2-HGA).
Identify tumor suppressors silenced by 2-HG
Identify more proteins modified by hydroxylation……
How do IDH1/2 mutations influence metabolism of fatty acids and amino acids
2-HGA
L-2-hydroglutaric acidura (L2HGA)
D-2-hydroglutaric acidura (D2HGA)
Combined 2-Hydroxyglutaric Aciduria
(D,L-2-HGA)
Type Ⅰ （50%）
Type Ⅱ （50%）
Genetic cause L2HGDH inactive muation D2HGDH inactive muation
Conversion of L-2-HG to 2-KG by L-2-HGDH
L-2-HGDH: L-2-hydroxyglutarate dehydrogenase enzyme
L2HGDH mutations: the molecular basis of L-2HGA
Conversion of D-2-HG to 2-KG by D-2-HGDH
cerebellar ataxia… abnormal brain MRI Increase urinary organic acids in body fluids (GC-MS): plasma,
cerebrospinal fluid, urine
2-hdroxyglutaric aciduria (2-HGA)
Origin of the D- and L-2-hydroglutarate
L-malDH: L-malate dehydrogenase enzyme; HOT:hydroxyacid-oxoacid transhydrogenase enzyme; GHB: γ-hydroxybutyrate; SSA: succinic semialdehyde
IDH2 mutations: the molecular basis of D-2-HGA type Ⅱ
Novel IDH2-mutant gain-of-function produces D-2-HG from 2-KG in addition to production of D-2-HG via HOT. It is hypothesized that D-2-HGDH cannot fully metabolize all of the generated D-2-HG, resulting in D-2-HG accumulation in D-2-HGA type II
Dan Ye, Kun-Liang Guan et al., Cancer Cell, 23, March 18, 2013
5 methyl-cytosine hydoxylase DNA demethylase RNA demethylase
Histone demethylase
Prolyl-4-hydoxylase
2-HG occupies the same space as α-KG does in the active site of histone demethylases.
Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation.
Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria
Benjamin et al., The American Journal of Human Genetics 92, 627–631, April 4, 2013