Browsing Pathways

Gliclazide is a sulfonylurea drug used in the treatment of type 2 diabetes. Gliclazide 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. Gliclazide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.

Inositol phosphates are a group of molecules that are important for a number of cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. Inositol phsosphates consist of an inositol (a sixfold alcohol of cyclohexane) phosphorylated at one or more positions. There are a number of different inositol phosphates found in mammals, distinguishable by the number and position of the phosphate groups. Inositol phosphate can be formed either as a product of phosphatidylinositol phosphate metabolism or from glucose 6-phosphate via the enzyme inositol-3-phosphate synthase 1. Conversion between the different types of inositol phosphates then occurs via a number of specific inositol phosphate kinases and phosphatases, which add (kinase) or remove (phosphatase) phosphate groups. The differing roles of the numerous inositol phosphates means that their metabolism must be tightly regulated. This is done via the localization and activation/deactivation of the various kinases and phosphatases, which can be found in the cytoplasm, nucleus or endoplasmic reticulum. The unphosphorylated inositol ring can be used to produce phosphoinositides through phosphatidylinositol phosphate metabolism.

Phosphatidylinositol phosphates, or phosphoinositides, are intracellular signaling lipids. Seven different phosphoinositides have been identified in mammals, each distinguished by the number and/or position of the phosphate groups on the inositol ring. The inositol can be mono-, di-, or triphosphorylated, with the remaining phosphoinositides being isomers of these three forms. Phosphoinositides regulate a variety of signal transduction processes, thus playing a number of important roles in the cell, such as actin cytoskeletal reorganization, membrane transport, and cell proliferation. They may also affect protein localization, aggregation, and activity by acting as secondary messengers. The ability of the cell to recognize the different types of phosphoinositides as different cellular signals means that their synthesis and metabolism must be tightly regulated. Synthesis begins with the attachment of an inositol phosphate head group to diacylglycerol via a phospholipase C enzyme, creating a phosphoinositide. Conversion between the different types of phosphoinositides is then done by a number of specific phosphoinositide kinases and phosphatases, which add (kinase) and remove (phosphatase) phosphates from the inositol ring. The specific localization and regulation of the phosphoinositide kinases and phosphatases thus controls the activity of the phosphoinositides. While the phosphoinositides are always located in the membrane, their particular kinases and phosphatases may be found in the cytoplasm or in the membrane of the cell or cell organelles.

Vitamin K describes a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and synthetically in three others): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofacter in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NAD(P)H dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To complete the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include a number of important coagulation factors, such as prothrombin. Thus, warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase.

Carnitine is an ammonium compound that exists in two stereoisomers, of which only L-carnitine is biologically active. Carnitine can be obtained from dietary sources and also biosynthesized. It is necessary for fatty acid oxidation, transporting fatty acids from the cystosol to the mitochondria, where they are broken down via the citric acid cycle to release energy. Carnitine is synthesized from lysine residues in existing proteins. These residues are methylated using lysine methyltransferase enzymes and methyl groups from S-adenosylmethionine, then removed from the protein via hydrolysis. In the next step, the N6,N6,N6-trimethyl-L-lysine is converted to 3-hydroxy-N6,N6,N6-trimethyl-L-lysine t via the mitochondrial enzyme trimethyllysine dioxygenase. The 3-hydroxy-N6,N6,N6-trimethyl-L-lysine is then cleaved to 4-trimethylammoniobutanal and glycine, likely by an aldose identical to serine hydroxymethyltransferase. Next, 4-trimethylammoniobutanal is oxidized by the 4-trimethylaminobutyraldehyde dehydrogenase protein to 4-trimethylammoniobutanoic acid. Finally, 4-trimethylammoniobutanoic acid is transformed into L-carnitine via the enzyme gamma-butyrobetaine dioxygenase. The reactions in the carnitine synthesis pathway occur ubiquitously in the human body with the exception of the last step, as the gamma-butyrobetaine dioxygenase enzyme is found only in the liver and kidney (and at very low levels in the brain). The produced carnitine is then carried to other tissue via a number of transport systems.

Acetyl-CoA is an important molecule, which is precursor to HMG CoA, which is a vital component in cholesterol and ketone synthesis. Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Acetyl-CoA is made in the mitochondria by metabolizing fatty acids, and the oxidation of pyruvate of acetyl-CoA. When the body has an excess of ATP, the energy in acetyl-Coa can be stored in the form of fatty acids. Acetyl-CoA must cross the mitochondrial membrane to the cytosol, where fatty acid synthesis takes place. Acetyl-CoA is combined with oxalacetic acid by the enzyme citrate synthase, creating citric acid. Citric acid is then transported out of the mitochondria, to the cytosol, where the enzyme citrate lyase converts citric acid back into acetyl-CoA and oxalacetic acid. Malate dehydrogenase reduces oxalacetic acid to malate, which then is either transported back into the mitochondria by the malate-alpha ketoglutarate transporter or oxidized to pyruvate by malic enzyme. Pyruvate can then be transported back into the mitochondria and undergo decarboxylation into oxalacetic acid. Malate can also be used to create NADH by the conversion of malate to oxalacetic acid by malate dehydrogenase.

Trehalose, also known as mycose or tremalose, is a sugar consisting of two 1-1 alpha bonded glucose molecules. It is produced by some plants, bacteria, fungi and invertebrates, and can be used as a source of energy, such as for flight in insects, and as a survival mechanism to avoid freezing and dehydration. After ingestion in the intestine lumen, trehalose can interact with trehalase, which exists in the brush border of the cells there. In a reaction that also requires a water molecule, it is broken. These are then transported into the epithelial cells along with a sodium ion by a sodium/glucose cotransporter, which can bring glucose up its gradient along with sodium moving down its gradient. Once inside the cell, the glucose can then be transported out of the basolateral membrane by a solute carrier family 2 facilitated glucose transporter. From there, the glucose enters the blood stream, and is transported to liver hepatocytes. Once in the liver, glucokinase can use the energy and phosphate from a molecule of ATP to form glucose-6-phosphate, which then goes on to start the process of glycolysis.

Reactive oxygen species (ROS) are formed by the normal metabolic process of oxygen. Examples are superoxide, oxygen ions and peroxides and can be of either organic or inorganic origin. ROS are highly reactive due to unpaired valence shell electrons, and can cause serious damage to cells and cell organelles. The environment also may cause ROS to form, from sources such as drought, air pollutants, UV light, cold temperatures, and external chemicals. An organic example of ROS being formed is during the beta oxidation of fatty acids, or photorespiration in photosynthetic organisms. Aerobic organisms who produce energy through the electron transport chain in mitochondria produce ROS as a byproduct. ROS damage commmonly includes DNA damage, lipid peroxidation, oxidation of amino acids in proteins, and oxidatively inactivating enzymes by oxidation of cofactors. Most aerobic organisms have adapted to this dangerous condition of life, and have a system of enzymes and scavenging free radicals. Enzymes such as are essential for defense against ROS, and include superoxide dismutases (SODs) and hydroperoxidase (CAT). Superoxide dismutases are the primary method of disposal of ROS, and convert superoxide radicals to hydrogen peroxide and water. Catalase attacks the hydrogen peroxide produced by SODs, and converts it into oxygen and water. In skin cells, 5,6 dihydroxyindole-2-carboxylic acid oxidase in the melanosome membranes breaks down hydrogen peroxide into water and oxygen.

Capecitabine is a fluoropyrimidine anticancer drug. After absorption, it is metabolized in the liver to the intermediate 5’-deoxy-5-fluorouridine, which is subsequently converted into 5-fluorouracil (5-FU) by intracellular thymidine phosphorylase. 5-FU exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase. Since thymidine phosphorylase is present at 3-10 fold higher concentration in cancer cells compared normal cells, capecitabine’s cytotoxic effect is selective for cancer cells.

Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a fluoropyrimidine anticancer drug. By injection into a vein, it is used to treat colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream, it is used for actinic keratosis, basal cell carcinoma, and skin warts. Fluorouracil is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system . Fluorouracil exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase.