Browsing Pathways

Piroxicam (also named Feldene or Piroxicamum) is a nonsteroidal anti-inflammatory drug. Piroxicam can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of piroxicam. Piroxicam can prevent movement of leukocytes to inflammation site so that thromboxane A2 can't be produced.

Thiamine, (Vitamin B1), is a compound found in many different foods such as beans, seafood, meats and yogurt. It is usually maintained by the consumption of whole grains. It is an essential part of energy metabolism. This means that thiamine helps convert carbohydrates into energy. Eating carbohydrates increases the need for this vitamin, as your body can only store about 30mg at a time due to the vitamins short half-life. Thiamine was first synthesized in 1936, which was very helpful in researching its properties in relation to beriberi, a vitamin b1 deficiency. This deficiency has been observed mainly in countries where rice is the staple food. Thiamine metabolism begins in the extracellular space, being transported by a thiamine transporter into the cell. Once in the intracellular space, thiamine is converted into thiamine pyrophosphate through the enzyme thiamin pyrophosphate kinase 1. Thiamine pyrophosphate is then converted into thiamine triphosphate, again using the enzyme thiamin pyrophosphatekinase 1. After this, thiamine triphosphate uses thiamine-triphosphatase to revert to thiamine pyrophosphate, which undergoes a reaction using cancer-related nuceloside-triphosphatase to become thiamine monophosphate. This phosphorylated form is a metabolically active form of thiamine, as are the two other compounds, derivatives of thiamine, mentioned previously. The enzymes used in this pathway both stem from the upper small intestine. Thiamine is passed mainly through urine. It is a water-soluble vitamin, which means it dissolves in water and is carried to different parts of the body but is not stored in the body.

This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.

Retinol is part of the vitamin A family, and is known as vitamin A1, and in a dietary context it is a type of preformed vitamin A. As with other preformed vitamin A's, it can be obtained from animal sources, with the highest concentrations coming from animal liver, with other sources being fish and dairy products. Other forms of vitamin A include retinal, its aldehyde form, retinoic acid, its acid form, and reinyl ester, its ester form. Additionally, herbivores and omnivores can obtain provitamin A from things such as alpha-, beta- and gamma-carotene, which can be converted to retinol as needed by the body. Retinol can be used in the body to form retinyl ester via diacylglycerol O-acyltransferase 1 and acyl-CoA wax akcohol acyltransferase 1 which both use acetyl-CoA as a reactant and produce CoA in addition to the retinyl ester. IT can also be produced by lecithin retinol acyltransferase, which uses a phosphatidylcholine molecule, and produces glycerophosphocholine. All of these reactions take place in the endoplasmic reticulum. Retinyl ester can also be converted back to retinol by patatin-like phospholipase domain-containing protein 4 as the enzyme in a reaction that also converts a diacylglycerol to a triacylglycerol. Alternately, retinyl ester can interact with retinoid isomerohydrolase to form 11-cis-retinol. 11-cis-retinol can be converted to retinyl palmitate by either diacylglycerol O-acyltransferase 1 or acyl-CoA wax alcohol acyltransferase 1 in the endoplasmic reticulum, which both add the acetyl group onto 11-cis-retinol, forming CoA as a side product. Alternatively, retinyl palmitate can be formed by lecithin retinol acyltransferase, which takes a molecule of phosphatidylcholine, and produces glycerophosphocholine in addition to the retinyl palmitate. Rhodopsin, a photosensitive protein found in the retina, can be converted to bathorhodopsin, which has previously been known as prelumirhodopsin. This conversion is caused by the absorption of light into the retinal portion of the protein complex, which then isomerizes, forcing the protein to change shape to accomodate this. Bathorhodopsin almost immediately converts to lumirhodopsin, which then converts to metarhodopsin, and at this point, the retinal is in its all-trans configuration. All-trans retinal can also be formed from 11-cis-retinaldehyde, also known as 11-cis-retinal, via dehydrogenase/reductase SDR family member 4 or retinol dehydrogenase 12 in the cell, as well as retinol dehydrogenases 8 and 16, short-chain dehydrogenase/reductase 3 or dehydrogenase/reductase SRD family member 9 in the endoplasmic reticulum. Two molecules of retinal can also be formed from beta-carotene, after its interaction with betabeta-carotene 15,15'-monooxygenase, or from retinol via retinol dehydrogenase 11 in the endoplasmic reticulum. Additionally, 11-cis-retinaldehyde can reversibly form all-trans retinal via interaction with alcohol dehydrogenase 1A. 11-cis-retinaldehyde is also in the conformation found in rhodopsin, and can be used to create more rhodopsin complexes. 11-cis-retinaldehyde can also be converted to 11-cis-retinol by retinol dehydrogenase in the endoplasmic reticulum. Retinol can also isomerize and form 9-cis-retinol, which can then be reversibly oxidized to form 9-cis-retinal by interacting with either retinol dehydrogenase 11 or dehydrogenase/reductase SDR family member 4. 9-cis-retinal can then be further oxidized to 9-cis-retinoic acid by retinal dehydrogenase 1 or 2. 9-cis-retinoic acid can also be formed from the isomerization of all-trans retinoic acid, which in turn is formed by the oxidation of retinol by either of retinal dehydrogenase 1 or 2. All-trans retinoic acid can also be glucuronidated to form retinoyl b-glucuronide, in a reaction catalyzed by a multiprotein chaperone complex including UDP-glucuronosyltransferase 1-1 in the endoplasmic reticulum. Finally, in the endoplasmic reticulum, all-trans-retinoic acid can undergo epoxidation to form all-trans-5,6-epoxyretinoic acid by interaction with a complex of cytochrome P450 proteins, or hydroxylated to either 4-hydroxyretinoic acid or all-trans-18-hydroxyretinoic acid by cytochrome P450 26A1. In one last reqction, 4-hydroxyretinoic acid can be oxidized once again by cytochrome P450 26A1 to form 4-oxo-retinoic acid.

Butyrate metabolism (Butanoate metabolism) describes the metabolic fate of a number of short chain fatty acids or short chain alcohols that are typically produced by intestinal fermentation. Many of these molecules are eventually used in the production of ketone bodies, the creation of short-chain lipids or as precursors to the citrate cycle, glycolysis or glutamate synthesis. The molecule for which this pathway is named, butyric acid, is a four-carbon fatty acid that is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber). It is found in rancid butter, parmesan cheese, and vomit, and has an unpleasant odor and acrid taste, with a sweet aftertaste (similar to ether).

Glutamate is one of the non-essential amino acids that is produced by the body. Glutamate is precursor for many nucleic acids and proteins in addition to its role in the central nervous system. It is an excitatory neurotransmitter and has a role in neuronal plasticity, affecting memory and learning. Glutamate plays a role in numerous metabolic pathways. Dysfunctional glutamate metabolism may cause disorders such as: gyrate atrophy, hyperammonemia, γ-hydoxybutyric aciduria, hemolytic anemia, and 5-oxoprolinuria.

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation. Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.

Riboflavin (vitamin B2) is an important part of the enzyme cofactors FAD (flavin-adenine dinucleotide) and FMN (flavin mononucleotide). The name "riboflavin" actually comes from "ribose" and "flavin". Like the other B vitamins, riboflavin is needed for the breaking down and processing of ketone bodies, lipids, carbohydrates, and proteins. Riboflavin is found in many different foods, such as meats and vegetables.As the digestion process occurs, many different flavoproteins that come from food are broken down and riboflavin is reabsorbed. The reverse reaction is mediated by acid phosphatase 6. FMN can be turned into to FAD via FAD synthetase, while the reverse reaction is mediated by nucleotide pyrophosphatase. FAD and FMN are essential hydrogen carriers and are involved in over 100 redox reactions that take part in energy metabolism.

This pathway describes the inactivation and catabolism of male (androgen) and female (estrogen) hormones. Many steroid hormones are transformed by sulfatases, dehydrogenases and glucuronide transferases to enhance their solubility and to facilitate their elimination. Inactivation means to convert an active compound into an inactive compound. Peripheral inactivation, which is inactivation caused by outside enzymes such as liver enzymes for example, is needed to maintain a steady-state level of plasma. This means that if either of these hormones are to be “chemical signals”, their half-life in the bloodstream has to be limited so that a variation in secretion rate can be emulated in the plasma. A large part of inactivation/catabolism occurs in the liver, although a little bit of catabolic activity does happen in the kidneys. Inactive androgens and estrogens are mostly eliminated in the urine. For this to happen, androgen and estrogen need to be converted to compounds that are less hydrophobic so that they are more soluble at higher concentrations. In this pathway, the conversion to a hydrophilic compound is an oxidation of a 17b-hydroxyl group. These hormones are needed for sexual development in both males and females.

Aspartate is synthesized by transamination of oxaloacetate by aspartate aminotransferase or amino acid oxidase. Aspartyl-tRNA synthetase can then couple aspartate to aspartyl tRNA for protein synthesis. The aspartate content in human proteins is about 7%. Asparagine synthase can convert aspartate to the polar amino acid asparagine. Aspartate is also a precursor for cellular signaling compounds such as, N-acetyl-aspartate, beta-alanine, adenylsuccinate, arginino-succinate and N-carbamoylaspartate. Aspartate is also a metabolite in the urea cycle and involved in gluconeogenesis. Additionally, aspartate carries the reducing equivalents in the mitochondrial malate-aspartate shuttle, which utilizes the ready interconversion of aspartate and oxaloacetate. The conjugate base of L-aspartic acid, aspartate, also acts as an excitatory neurotransmitter in the brain which activates NMDA receptors.