Browsing Pathways

Adult Refsum Disease (Classic Refsum Disease; Phytanic Acid Oxidase Deficiency; Heredopathia Atactica Polyneurtiformis; Hereditary Motor and Sensory Neuropathy IV; HSMN4; Adult Refsum Disease I; Adult Refsum Disease II), can be caused by mutations in the PHYH (or PAHX) gene, which encodes Phytanoyl-CoA hydroxylase (, the first enzyme in the Phytanic Acid Peroxisomal Oxidation pathway) on chromosome 10 (adult Refsum disease I), and by mutation of the PEX7 gene. A defect in phytanoyl-CoA hydroxylase results in accumulation of phytanic acid in the plasma, as well as low levels of pristanic acid due to the inability for phytanic acid to undergo alpha and beta oxidation. Symptoms include anosmia, ataxia, nystagmus, neurological deterioration and peripheral neuropathy. Adult Refsum disease is distinctly different from Infantile Refsum disease both genetically and phenotypically. Infantile Refsum disease involves mutations of the PEX1, PEX2 and PEX26 genes.

2-oxobutanoate, also known as 2-Ketobutyric acid, is a 2-keto acid that is commonly produced in the metabolism of amino acids such as methionine and threonine. Like other 2-keto acids, degradation of 2-oxobutanoate occurs in the mitochondrial matrix and begins with oxidative decarboxylation to its acyl coenzyme A derivative, propionyl-CoA. This reaction is mediated by a class of large, multienzyme complexes called 2-oxo acid dehydrogenase complexes. While no 2-oxo acid dehydrogenase complex is specific to 2-oxobutanoate, numerous complexes can catalyze its reaction. In this pathway the branched-chain alpha-keto acid dehydrogenase complex is depicted. All 2-oxo acid dehydrogenase complexes consist of three main components: a 2-oxo acid dehydrogenase (E1) with a thiamine pyrophosphate cofactor, a dihydrolipoamide acyltransferase (E2) with a lipoate cofactor, and a dihydrolipoamide dehydrogenase (E3) with a flavin cofactor. E1 binds the 2-oxobutanoate to the lipoate on E2, which then transfers the propionyl group to coenzyme A, producing propionyl-CoA and reducing the lipoate. E3 then transfers protons to NAD in order to restore the lipoate. Propionyl-CoA carboxylase transforms the propionyl-CoA to S-methylmalonyl-CoA, which is then converted to R-methylmalonyl-CoA via methylmalonyl-CoA epimerase. In the final step, methylmalonyl-CoA mutase acts on the R-methylmalonyl-CoA to produce succinyl-CoA.

Nateglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, nateglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Nateglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with nateglinide therapy compared to sulfonylureas.

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.

Homocysteine is an amino acid and homologue of cysteine that appears in the body as a result of the degradation of methionine. In mammals, homocysteine is used to biosynthesize cysteine via the following pathway. First the enzyme cystathionine beta-synthetase irreversibly condenses homocysteine with L-serine, forming L-cystathionine. The L-cystathionine is then cleaved by cystathionine gamma-lyase, producing 2-oxobutanoate, L-cysteine, and ammonia. The 2-oxobutanoate is further broken down via the 2-oxobutanoate degradation pathway, producing citric acid cycle intermediates, while the L-cysteine goes to the cysteine metabolism pathway. The homocysteine degradation pathway composes a part of the larger methionine metabolism pathway.

The biosynthesis of fatty acids primarily occurs in liver and lactating mammary glands. The entire synthesis process which produces palmitic acid occurs on a multifunctional dimeric protein Fatty Acid Synthase (FA) in the cytosol. The production of palmitic acid can be summarized as the successive addition of two carbons to an initial acetyl moiety primer. After 7 cycles palimitic acid is released. The synthesis starts with the sequential transfer of a primer substrate, acetyl-CoA, to the nucleophilic serine residue of the acyltransferase domain of FA. The acetyl moiety is then transferred to the Acyl Carrier Protein (ACP) domain of FA, then finally to the active site of the beta-ketoacyl synthase domain. A chain extender substrate, molonyl-CoA, is transferred to the nucleophilic serine residue of the acyltransferase domain and subsequently to the ACP domain. The acetyl moiety is extend by a condensation reaction, catalysed by the beta-ketoacyl synthase domain, that produces a new Carbon-Carbon bound, this reaction is coupled to a decarboxylation resulting in the production of carbon dioxide. Subsequently beta-ketoacyl condensation product is reduced to a saturated acyl moiety through the step wise action on the beta-ketoacyl reductase, beta-hydroxyacyl dehydrase and enoyl reductase domains respectively. This saturated acyl moiety is then transfer back to the active site of the beta-ketoacyl synthase domain, another molonyl-CoA is loaded and the process repeats. The addition of molonyl moieties occurs 7 times after which the final product is released by that action of thioesterase domain. The final product is 16 carbon long palmitic acid.

Lactose degradation (Lactose metabolism) shows the breakdown of alpha lactose into its constituent sugars, which are then utilized by the body as an energy source. Alpha-Lactose is the major sugar present in milk and the main source of energy supplied to the newborn mammalian in its mother’s milk. Lactose is also an important osmotic regulator of lactation. It is digested by the intestinal lactase, an enzyme expressed in newborns. Its activity declines following weaning. Lactase hydrolyzes alpha lactose into D-glucose and D-galactose, which are actively transported into the intestinal epithelial cells via the SGLT1 (GLUT1) cotransporter. GLUT1 actively transports glucose and galactose with 2 sodium ions. A sodium/potassium ATPase makes ATP by moving three sodium ions to the blood per two potassium ions that cross into the epithelial cell, giving the GLUT1 transporter energy to work. D-glucose and D-galactose diffuse into the blood, facilitated by the SLC2A2 transporter on the basolateral membrane on the intestinal epithelial cells. The sugars are then transported to liver.

Lactose intolerance is a condition in which the body does not support the ingestion of lactose through the consumption of milk, cheese, and other dairy products. This intolerance occurs due to the lack of the enzyme intestinal lactase, which is an enzyme found in newborns. The frequency of this enzyme declines rapidly after the child stops breastfeeding. Lactase deficiency is most prevalent in Asia, Africa and Indigenous populations in North and South America. The symptoms of lactose intolerance include diarrhea, bloating, abdominal pain and excessive flatus. The cause of these symptoms is the processing of the ingested lactose being fermented by intestinal bacteria instead of in the small intestine, where lactose is meant to be processed.

This Pyruvaldehyde degradation pathway (Methylglyoxal degradation;2-oxopropanal degradation), also known as the glyoxalase system, is probably the most common pathway for the degradation of pyruvaldehyde (methylglyoxal), a potentially toxic metabolite due to its interaction with nucleic acids and other proteins. Pyruvaldehyde is formed in low concentrations by glycolysis, fatty acid metabolism and protein metabolism. Pyruvaldehyde is catalyzed by the glyoxylase system, composed of the enzymes lactoylglutathione lyase (glyoxalase I) and glyoxylase II. Glyoxalase I catalyes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and pyruvaldehyde into S-lactoylglutathione. S-lactoylglutathione is then catalyzed by glyoxalase II into D-lactic acid and glutathione. D-lactic acid is then catalyzed by an unknown quinol in the membrane to pyruvic acid, which then enters pyruvate metabolism.

Glibenclamide is a sulfonylurea drug used in the treatment of type 2 diabetes. Glibenclamide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Glibenclamide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.