Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
The Oncogenic Action of D-2-Hydroxyglutarate in Hydroxyglutaric aciduria
Homo sapiens
Disease Pathway
Hydroxyglutaric aciduria is a rare genetic disorder. Both isoforms are believed to have autosomal recessive inheritance. The compound 2-hydroxyglutarate is the product of gain-of-function mutations producing mutIDH1 and mutIDH2 in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). This compound is derived from the TCA cycle. The compound 2-hydroxyglutarate shares structural similarity with 2-oxogluratate (2OG) to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This results in modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. 2-Hydroxyglutarate dehydrogenase (D2HGDH) converts D-2-hydroxyglutarate (D-2HG) to α-ketoglutaric acid. The enzyme D-3-phosphoglycerate dehydrogenase (PHGDH) catalyzes the NADH-dependent reduction of α-ketoglutarate (AKG) to D-2HG. D-2-Hydroxyglutarate is an oncometabolite produced from IDH mutations. A mutation in IDH causes high concentrations of D-2-Hydroxyglutaric acid. D-2-hydroxyglutarate is a competitive inhibitor of 2OG-dependent dioxygenases resulting in genetic changes and malignancies.
References
The Oncogenic Action of D-2-Hydroxyglutarate in Hydroxyglutaric aciduria References
Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, Rabinowitz JD: Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015 Feb 20;10(2):510-6. doi: 10.1021/cb500683c. Epub 2014 Nov 18.
Pubmed: 25406093
Ma S, Jiang B, Deng W, Gu ZK, Wu FZ, Li T, Xia Y, Yang H, Ye D, Xiong Y, Guan KL: D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget. 2015 Apr 20;6(11):8606-20. doi: 10.18632/oncotarget.3330.
Pubmed: 25825982
Adam J, Yang M, Soga T, Pollard PJ: Rare insights into cancer biology. Oncogene. 2014 May 15;33(20):2547-56. doi: 10.1038/onc.2013.222. Epub 2013 Jul 1.
Pubmed: 23812428
Owens WE, Okun MS: Dystonia, tremor, and parkinsonism in a 54 year old man with 2-hydroxyglutaric aciduria. J Neurol Neurosurg Psychiatry. 2004 Sep;75(9):1362-3. doi: 10.1136/jnnp.2003.033571.
Pubmed: 15314137
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Settings