Browsing Pathways

Hypoxia-inducible factor In many tumours, oxygen availability becomes limited (hypoxia) very quickly during cancer development. The major regulator of the response to hypoxia is the HIF transcription factor. Under normal oxygen levels, the protein levels of HIF alpa is very low due to constant degradation, mediated by a sequence of post-translational modification events catalyzed by the enzymes PHD1,2 and 3, (also known as EglN2,1 and 3). Under hypoxic conditions, HIF alpha escapes hydroxylation and degration. Succinate dehydrogenase (SDH) is a collection of housekeeping genes (SDHA,B,C,D), but mutations in those genes allows for succinate to accumulate and cross the mitochondrial barrier through a dicarboxylate carrier. Once in the cytosol, it inhibits the activity of the PHD1,2 and 3 since succinate is a product of the enzyme, it acts as feedback inhibition.

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 enough structural similarity to 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. L-2-hydroxyglutarate dehydrogenase (L2HGDH) converts L-2-hydroxyglutarate to α-ketoglutaric acid. L-2-Hydroxyglutarate is an oncometabolite and is produced by gain-of-function IDH mutations. When IDH is mutated, L-2-Hydroxyglutaric acid production is increased. L-2-hydroxyglutarate is a competitive inhibitor of 2OG-dependent dioxygenases resulting in genetic changes and malignancies.

Hypoxia-inducible factor In many tumours, oxygen availability becomes limited (hypoxia) very quickly during cancer development. The major regulator of the response to hypoxia is the HIF transcription factor. Under normal oxygen levels, the protein levels of HIF alpa is very low due to constant degradation, mediated by a sequence of post-translational modification events catalyzed by the enzymes PHD1,2 and 3, (also known as EglN2,1 and 3). Under hypoxic conditions, HIF alpha escapes hydroxylation and degration. Fumarate hydratase (FH) is a housekeeping gene, but mutations in this gene allows for fumarate to accumulate and cross the mitochondrial barrier through a dicarboxylate carrier. Once in the cytosol, it inhibits the activity of the PHD1,2 and 3 since it is chemically similar to succinate. Having a double bond in the centre of the dicarboxylic acid, fumarate is a rigid molecule compared to succinate making it a probable possibility for fumarate to interacts better with PHDs.

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.

2-Hydroxyglutarate is a compound formed from isocitric acid, a component of the TCA cycle. Isocitric acid becomes dehydrogenated by isocitrate dehydrogenase using NADP as a cofactor, and forming oxoglutaric acid. Oxoglutaric acid then forms 2-hydroxyglutarate in a reaction catalyzed by a mutant isocitrate dehydrogenase 2 enzyme, which also uses NADP as a cofactor. Normally, the isocitrate dehydrogenase 2 enzyme, encoded by the IDH2 gene, is responsible for the formation of 2-oxoglutaric acid from isocitrate. However, some gain-of-functions mutations to the IDH2 gene allow the enzyme to produce 2-hydroxyglutarate instead. This functionality is associated with several types of cancer, including glioma and acute myeloid leukemia. This is due to the buildup of 2-hydroxyglutarate, which inhibits several enzymes which rely on 2-oxoglutaric acid, such as methylcytosine dioxygenase and lysine-specific demethylase 2A. Both of these enzymes use 2-oxoglutarate to demethylate DNA, and when repressed, allow DNA to become hypermethylated. This in turn changes which genes are normally expressed, as methylation is used to suppress genes, and can lead to the expression of oncogenes or the repression of tumor-suppressing genes. This is the effect responsible for 2-hydroxyglutarate in cancer and other diseases.

Metabolites of Thalidomide are predicted with biotransformer.