Browsing Pathways

Ibuprofen is a very common NSAID drug used to treat pain and inflammation. This includes headaches, muscle pain and fever. It is sold under the brand name Advil or Motrin. Ibuprofen is typically ingested orally, although in the USA an intravenous version can be used. It inhibits cyclooxygenase (COX) non-selectively. This enzyme is responsible for the creation of prostaglandins, which allow pain to be felt. Inhibiting COX makes prostaglandin creation more sparse, thus resulting in less pain for the patient using ibuprofen. Arachdonic acid is converted into prostaglandin H2 by using cytosolic prostaglandin G/H synthase (COX). These enzymes are available as COX1 and COX2, and are encoded by PTGS1 (COX1) and PTGS2 (COX2). Ibuprofen may also inhibit fatty acid amide hydrolase (FAAH), which results in the activation of antinociceptive axis, which then metabolizes the endocannabinoid anandamide.

Nabumetone (also named Relafen and Relifex) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic) and reduce fever (antipyretic). Nabumetone 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. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain, fever and inflammation.

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) that can be used to treat rheumatoid arthritis and osteoarthritis. Most NSAIDs are non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitors that act on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. NSAIDs antagonize COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased prostaglandin synthesis. Etodolac was previously thought to be a non-selective COX inhibitor; however, it is now know that it is five to fifty times more selective for COX-2 than COX-1. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of etodolac. The latter portion of this figure depicts etodolac’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Etodolac preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.

Sulindac, sold as Clinoril, is a non-steroidal anti-inflammatory drug (NSAID). These drugs are typically used to treat conditions associated with pain and inflammation, such as rheumatoid arthritis, headaches or migraines, and dysmenorrhoea. Sulindac is believed to be a non-selective NSAID, meaning that it inhibits both prostaglandin G/H synthase 1 and 2 (COX-1 and COX-2). In this pathway, sulindac, a prodrug, is administered orally. Once in the body, it is metabolized to form the active form of sulindac, which then inhibits the COX-1 and COX-2 enzymes. These enzymes are normally responsible for the formation of prostaglandin G2 from arachidonic acid, well as the formation of prostaglandin H2 from prostaglandin G2. These prostaglandins are responsible for inflammation and fever, as well as muscle contractions in labour and menstruation. With the COX-1 and COX-2 enzymes being inhibited by sulindac, prostaglandins cannot be produced, and inflammation and fever can be reduced. Compared to other NSAIDs, sulindac is less likely to damage the kidneys and cause gastrointestinal effects such as ulcers, but is more likely to damage the liver and pancreas.

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.

Momoamine oxidase A (MAO-A) deficiency, or Brunner syndrome, is an X-linked recessive genetic disorder caused by a mutation in the MAOA gene that encodes for monoamine oxidase A. As such it is almost exclusively found in men. MAO-A is an enzyme that catalyzes the deamination of amines such as epinephrine, dopamine and tyramine, as part of the tyrosine metabolism pathway. In this disorder, some neurotransmitters such as serotonin and dopamine build up in the brain due to their inability to be properly metabolized. Since serotonin helps to regulate emotions and mood, with epinephrine and norepinephrine regulating stress, the unnecessary presence of the chemicals in the brain can lead to poor impulse control, aggression and other effects. The buildup of chemicals may also damage the brain, leading to a lower IQ in individuals with this disorder. In addition, foods containing the compounds that cannot be broken down, such as tyramine, can cause episodes of increased symptoms in the patients. In the subpathway that converts dopamine to homovanillic acid, there are two instances of MAO-A that are inactivated in this disorder, both in different branches. The first reaction converts dopamine to 3,4-dihydroxyphenylacetaldehyde, while the second converts 3-methoxytyramine to homovanillin. With the inactivation of MAO-A, 3-methoxytyramine builds up as there are no reactions that use it, and both of these paths lead to a decrease in the concentration of homovanillic acid, as there are no other reactions present that produce it. Another reaction, this time converting tyramine to homovanillin, is also prevented by the lack of MAO-A, which leads to an accumulation of tyramine in the body. In another branch of tyrosine metabolism, the absence of MAO-A prevents the oxidation of norepinephrine and epinephrine into 3,4-dihydroxymandelaldehyde. Its absence also prevents the oxidative deamination of metanephrine and normetanephrine into 3-methoxy-4-hydroxyphenylglycolaldehyde. As this is no longer produced, it leads to a decrease in the concentration of vanillylmandelic acid, which is produced from 3-methoxy-4-hydroxyphenylglycolaldehyde in a reaction catalyzed by aldehyde dehydrogenase.

Hawkinsinuria (4-Hydroxyphenylpyruvate Hydroxylase Deficiency) is an autosomal dominant disease caused by a mutation in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. A deficiency in this enzyme results in accumulation of hawkinsin in urine and plasma; cis-4-hydroxycyclohexylacetic acid, trans-4-hydroxycyclohexylaceid, vanillactic acid, 4-hydroxyphenylpyruvic acid, pyroglutamic acid in urine; and L-tyrosine in plasma. Symptoms include ketosis, metabolic acidosis, swimming-pool odor, and mental retardation. Treatment includes a low-protein diet and vitamin C.

Hyperphenylalaninemia due to dihydropteridine reductase deficiency (DHPR) is the high presence of phenylalanine in the system/blood caused by a genetic mutation. More specificially, mutations in the QDPR gene are the root cause of the condition. One observes that such a mutation results in an error encoding a reductase enzyme, and from there a chain reaction of effects lead to the observed effects of the disease. The mutation is autosomal recessive. When tetrahydrobiopterin levels drop, the breakdown of many several amino acids, such as phenylalanine, is reduced and as a result their levels in the blood augment. Symptoms of hyperphenylalaninemia due to dihydropteridine reductase deficiency include: dysphagia, global development delay, microcephaly, and intellectual disability (among others). Treatment consists of BH4 supplements as well as other medical treatments.

Sorafenib is a drug that belongs to the antineoplastics drug class, which is the drug class relating to the treatment of cancer, specifically renal, hepatic and thyroid cancers. This drug works by stopping cancerous tumour progress and stopping therapy replication pf potentially malignant cells. It does this by inhibiting protein synthesis, as we will explore in the pathway. Sorafenib is administered orally, in a tablet form taken twice daily without food. Once ingested, sorafenib finds itself in the endoplasmic reticulum membrane , where it inhibits cytochrome P450 2B6, cytochrome P450 2C8, cytochrome P450 2C9 and UDP-glucuronosyltransferase 1-1. Sorafenib is also catalyzed, with the help uridine diphosphate glucuronic acid and the enzyme UDP-glucuronosyltransferase 1-9 to sorafenib b-D-glucuronide with a by-product of uridine 5’-diphosphate. Sorafenib also undergoes a transformation without the use of catalytic enzymes and becomes sorafenib metabolite M4 and subsequently becomes sorafenib metabolite M5. In another reaction, sorafenib teams up with water and oxygen, using cytochrome P450 3A4 to create sorafenib N-oxide and hydrogen peroxide. Sorafenib N-oxide then undergoes two more reactions, one where it becomes sorafenib N-oxide glucuronide, and another where it becomes sorafenib metabolite M1. Sorafenib metabolite M1 is also attached to another reaction, as sorafenib creates sorafenib metabolite M3, sorafenib metabolite M1 is also created from this metabolite.

3-Phosphoglycerate dehydrogenase deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures.The disorder is caused by homozygous or compound heterozygous or homozygous mutation in the gene encoding phosphoglycerate dehydrogenase on chromosome 1p12. Defects in the gene lead to a decrease of Glycine and Serine.