PathWhiz

PathWhiz ID	Pathway	Meta Data
PW109814 View Pathway	disease The Oncogenic Action of 2-Hydroxyglutarate Rattus norvegicus 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. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: Ana Marcu Created On: August 31, 2018 at 15:53 Last Updated: August 31, 2018 at 15:53
PW002452 View Pathway	disease The Oncogenic Action of D-2-Hydroxyglutarate in Hydroxyglutaric aciduria Homo sapiens 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. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: miguel ramirez Created On: February 10, 2016 at 15:57 Last Updated: February 10, 2016 at 15:57
PW002363 View Pathway	disease The Oncogenic Action of Fumarate Homo sapiens 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. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: miguel ramirez Created On: November 19, 2015 at 09:58 Last Updated: November 19, 2015 at 09:58
PW002451 View Pathway	disease The Oncogenic Action of L-2-Hydroxyglutarate in Hydroxyglutaric aciduria Homo sapiens 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. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: miguel ramirez Created On: February 10, 2016 at 13:13 Last Updated: February 10, 2016 at 13:13
PW002508 View Pathway	disease The oncogenic action of Serine: serine, one carbon cycle glycine synthesis (SOG) Homo sapiens The SOG pathway is depicted as the combination of serine, one-carbon cycle and glycine cleavage all acting together in tumour cells. Glycolysis is upregulated in tumour cells, thus serine is synthesized from 3-phosphoglycerate whichis then coverted to glycine bya cytosolic serine hydroxymethyltransferase. Serine and glycine can also be transported into the mitochondria. Serine can be converted to glycine in the mitochondria where glycine can be incorporated into the glycine cleavage cycle. The serine reaction that yields glycine also produces 5,10-Methylene-THF which is incorporated into the one-carbon cycle. L-serine in mitochodria reacts with THF leading to the mitochondrial ne carbon cycle and the production of NADPH used in the transport of hydrogen ions into the mitochondria. ATP synthase is used to transport hydrogen outside of the mitochondria, generating ATP in the process. The SOG pathway is predicted to be mainly active in tumour cells with decreased activity from the pyruvate kinase protein. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: miguel ramirez Created On: March 23, 2016 at 13:44 Last Updated: March 23, 2016 at 13:44
PW002360 View Pathway	disease The Oncogenic Action of Succinate Homo sapiens 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. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: miguel ramirez Created On: November 17, 2015 at 10:45 Last Updated: November 17, 2015 at 10:45
PW230339 View Pathway	signaling The RAS-ERK and PI3K-mTOR signaling pathways Homo sapiens The RAS-ERK and PI3K-mTOR signaling pathways BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: Guest: Anonymous Created On: March 29, 2024 at 01:05 Last Updated: March 29, 2024 at 01:05
PW145582 View Pathway	drug action Thenalidine Drug Metabolism Action Pathway Homo sapiens BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: Ray Kruger Created On: October 07, 2023 at 16:08 Last Updated: October 07, 2023 at 16:08
PW063852 View Pathway	drug action Thenalidine H1-Antihistamine Action Homo sapiens Thenalidine is a piperidine H1-antihistamine that was withdrawn from Canadian, US, and UK markets in 1963 due to concerns involving neutropenia (DB04826). H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions. BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: Carin Li Created On: September 24, 2017 at 23:20 Last Updated: September 24, 2017 at 23:20
PW146952 View Pathway	drug action Thenyldiamine Drug Metabolism Action Pathway Homo sapiens BioPAX SVG SBGN SBML PWML All files (.zip)	Creator: Ray Kruger Created On: October 07, 2023 at 19:25 Last Updated: October 07, 2023 at 19:25