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PathWhiz ID Pathway Meta Data

PW122515

Pw122515 View Pathway
metabolic

Melanin Biosynthesis

Danio rerio
Melanin is used in the skin of zebrafish for camouflage, mimicry, communication and protection from the sun. It is also a pigment in the eyes. Melanin is produced by melanocytes, organelles within the skin cells. Eumelanins are brown and black pigments, while other melanins exist, pheomelanin being yellow and red pigments, and neuromelanin being used in the brain. All of these pigments require tyrosine to start their synthesis. To start this pathway, tyrosine is transported into the melanosome by an amino acid transporter, and at this point it is metabolized to L-dopachrome . Within the melanosome membrane, L-dopachrome tautomerase converts L-dopachrome to 5,6-dihydroxyindole-2-carboxylic acid. This then interacts with tyrosinase-related protein 1a, which adds an oxygen molecule to form 5,6-indolequinone-2-carboxylic acid. This then undergoes a final reaction to form eumelanin. Alternatively, L-dopachrome can spontaneously lose a carbon dioxide molecule, forming 5,6-dihydroxyindole. Following this, it can interact with tyrosinase to form indole-5,6-quinone. Finally, another reaction occurs, forming eumelanin from this compound.

PW002512

Pw002512 View Pathway
signaling

Melanocortin 1 receptor

Mus musculus

PW124207

Pw124207 View Pathway
metabolic

Melatonin Biosynthesis

Homo sapiens

PW145157

Pw145157 View Pathway
drug action

Melatonin Drug Metabolism Action Pathway

Homo sapiens

PW123950

Pw123950 View Pathway
metabolic

Meleagrin Biosynthesis

Penicillium rubens
Meleagrin is a roquefortine C-derived bioactive benzylisoquinoline alkaloid. Meleagrin and the other intermediates in this pathway are derived from deep ocean sediment-derived Penicillium species. It has other derivatives as well, oxaline for example. It is important in treating c-Met-dependent metastatic and invasive breast malignancies because of its top c-Met inhibitory action and antimicrobial as well as anti-proliferate abilities. This pathway is part of a larger pathway stemming from the compound tryptophan and shows the biosynthesis of meleagrin using a series of enzymes. The intermediate at which the pathway branches is roquefortine C. From the intermediate histidyltryptophyldiketopiperazine, the pathway illustrates two ways in which the pathways branching intermediate roquefortine C is synthesized. Both these ways each use the enzymes cytochrome P450 monooxygenase roqR and roquefortine prenyltransferase roqD in reversed order and via two different intermediates. The branching of the pathway from roquefortine C leads to either N1-hydroxy-roquefortine C or glandicoline A where glandicoline A is the direct way and N1-hydroxy-roquefortine C or glandicoline A acts as an intermediate route, both leading to the intermediate glandicoline B. This way shows that glandicoline A is not needed for the synthesis of glandicoline B and uses a novel intermediate roquefortine L. However, in both ways, the enzyme cytochrome P450 monooxygenase roqO has been used exculsively for glandicoline B synthesis. N1-hydroxy-roquefortine C also leads to the neoxaline biosynthesis - a compound belonging to the Aspergillaceae family and is known for its weak inhibitory activity of blood platelet aggregation induced by stimulation of the central nervous system of mice. Coming back to the main product of this pathway, glandicoline B goes on to synthesize meleagrin via the enzyme glandicoline B O-methyltransferase roqN.

PW000276

Pw000276 View Pathway
drug action

Meloxicam Action Pathway

Homo sapiens
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) with antipyretic and analgesic properties. Most NSAIDs, such as ibuprofen and naproxen, 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). COX catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2). PGH2 is the precursor to a number of prostaglandins (e.g. PGE2) involved in fever, pain, swelling and inflammation. Meloxicam antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Although it was previously thought that meloxicam is a non-selective COX inhibitor, it is now known that it has higher selectivity for COX-2. Selective COX-2 inhibitors are thought to have more potent anti-inflammatory and analgesic properties with decreased adverse gastric effects. The analgesic, antipyretic and anti-inflammatory effects of meloxicam occur as a result of decreased prostaglandin synthesis. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of meloxicam. The latter portion of this figure depicts meloxicam’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. Meloxicam 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.

PW144921

Pw144921 View Pathway
drug action

Meloxicam Drug Metabolism Action Pathway

Homo sapiens

PW126092

Pw126092 View Pathway
drug action

Meloxicam NSAID Action Pathway

Homo sapiens
Meloxicam is a nonsteroidal anti-inflammatory (NSAID) used to treat backache and ankylosing spondylitis. Meloxicam possesses anti-inflammatory, analgesic, and antipyretic activity. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Meloxicam inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because meloxicam decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects result in increased peripheral blood flow, vasodilation, and subsequent heat dissipation. This drug is administered as an oral tablet or as an intravenous injection.

PW176217

Pw176217 View Pathway
metabolic

Meloxicam Predicted Metabolism Pathway

Homo sapiens
Metabolites of Meloxicam are predicted with biotransformer.

PW145136

Pw145136 View Pathway
drug action

Melphalan Drug Metabolism Action Pathway

Homo sapiens