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Pathways

Showing 1 - 10 of 724 pathways
SMPDB ID Pathway Chemical Compounds Proteins

SMP02359

Pw002452 View Pathway
disease

The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria

Homo sapiens
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 is sufficiently similar in structure 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. In turn, this leads to modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. D-2-hydroxyglutarate can be converted to α-ketoglutaric acid through the action of 2-hydroxyglutarate dehydrogenase (D2HGDH). Additionally, the enzyme D-3-phosphoglycerate dehydrogenase (PHGDH) can catalyze the NADH-dependent reduction of α-ketoglutarate (AKG) to D-2-hydroxyglutarate (D-2HG). Nyhan et al. (1995) described 3 female patients, 2 of them sibs, who were found to have excess accumulation of D-2-hydroxyglutaric acid in the urine. The phenotype was quite variable, even among the sibs, but included mental retardation, macrocephaly with cerebral atrophy, hypotonia, seizures, and involuntary movements. One of the patients developed severe intermittent vomiting and was given a pyloromyotomy. The electroencephalogram demonstrated hypsarrhythmia. There was an increased concentration of protein in cerebrospinal fluid, an unusual finding in inborn errors of metabolism (OMIM #600721). D-2-Hydroxyglutaric acid is also considered to be an oncometabolite (or cancer-causing metabolite). It can be produced via gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). IDH is part of TCA cycle and this compound is generated in high abundance when IDH is mutated. D-2-hydroxyglutarate is sufficiently similar in structure to 2-oxogluratate (2OG) that it is able to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and members of the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This inhibitory effect leads to alterations in the hypoxia induced factor (HIF)-mediated hypoxic response and alterations in gene expression through global epigenetic remodeling. The net effect is that D-2-hydroxyglutarate causes a cascading effect that leads genetic perturbations and malignant transformation.

SMP02358

Pw002451 View Pathway
disease

The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria

Homo sapiens
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 is sufficiently similar in structure 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. In turn, this leads to modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. L-2-hydroxyglutarate can be converted to α-ketoglutaric acid through the action of L-2-hydroxyglutarate dehydrogenase (L2HGDH). L-2-Hydroxyglutaric acid is also considered to be an oncometabolite (or cancer-causing metabolite). It can be produced via gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). IDH is part of TCA cycle and this compound is generated in high abundance when IDH is mutated. L-2-hydroxyglutarate is sufficiently similar in structure to 2-oxogluratate (2OG) that it is able to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and members of the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This inhibitory effect leads to alterations in the hypoxia induced factor (HIF)-mediated hypoxic response and alterations in gene expression through global epigenetic remodeling. The net effect is that L-2-hydroxyglutarate causes a cascading effect that leads genetic perturbations and malignant transformation

SMP02313

Pw002387 View Pathway
disease

sarcosine oncometabolite pathway

Homo sapiens
Sarcosine levels have been found to be higher in prostate cancer cells. The expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), is elevated in cancer tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine.

SMP02298

Pw002366 View Pathway
disease

Glutaminolysis and Cancer

Homo sapiens
The glutaminolysis pathway catabolizes glutamine to generate ATP and lactate. Glutamine not only provides a major substrate for respiration but also for the synthesis of other macromolecules, such as nucleotides, proteins and hexosamines. It also macromolecule biosynthesis, glutaminolysis also has an important role in regulating redox balance, mTOR signaling, apoptosis and autophagy. High extracellular glutamine concentrations stimulate tumor growth and are essential for cell transformation. The transportation of glutamine in and out regulates mTOR activation to coordinate cell growth and proliferation. Glutaminolysis is a series of biochemical reactions by which glutamine is degraded into glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate. Glutamine is imported through ASCT2 and SN2, once inside the cell, it can be deaminated into glutamate. Glutamate is converted into Oxoglutaric acid which then is incorporated into the TCA cycle. Once it reaches malic acid, it is transported outside the mitochondria and transformed into pyruvic acid and lactate. The oxoglutaric acid can also be transformed into citric acid which then gets turned into acetyl coa and get incorporated into the lipid synthesis

SMP02295

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.

SMP02292

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.

SMP02291

Pw002359 View Pathway
disease

The oncogenic action of 2-hydroxyglutarate

Homo sapiens
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 is sufficiently similar in structure 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. In turn, this leads to modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation.

SMP00747

Pw000724 View Pathway
drug action

Zidovudine Action Pathway

Homo sapiens
Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA.

SMP00746

Pw000723 View Pathway
drug action

Zalcitabine Action Pathway

Homo sapiens
Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Within cells, zalcitabine is converted to its active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the sequential action of cellular enzymes. ddCTP interferes with viral RNA-directed DNA polymerase (reverse transcriptase) by competing for utilization of the natural substrate deoxycytidine 5'-triphosphate (dCTP), as well as incorpating into viral DNA.

SMP00745

Pw000722 View Pathway
drug action

Stavudine Action Pathway

Homo sapiens
Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Stavudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis.
Showing 1 - 10 of 724 pathways