Pathways

Ximelagatran is a prodrug that is converted to melagatran. This drug is a direct thrombin inhibitor that binds directly to the active site of thrombin, preventing coagulation and formation of blood clots due to the inactivation of the enzyme that catalyzes activation of coagulation factors V, XIII and fibrinogen. Ximelagatran is the first direct thrombin inhibitor that could be taken orally, and was thought to be a replacement for warfarin, due to not having as many dietary restrictions involved. However, it was withdrawn from testing and distribution following evidence of liver damage. After oral administration, ximelagatran is absorbed and converted to melagatran through an unknown series of reactions. From there, melagatran directly binds to thrombin, preventing its use as an enzyme. This prevents catalyzation of factor V to factor Va, which would form the prothrombinase complex and create more thrombin. It also prevents the catalysis fibrinogen or factor I to fibrin, which then polymerizes to form the blood clot. The lack of useable thrombin also prevents the catalysis of factor XIII to factor XIIIa, which is necessary to crosslink the polymerized fibrin to form a water insoluble clot.

Ximelagatran is an anticoagulant drug used to prevent and treat blood clots, and was the first drug in the anticoagulant drug class to be able to be ingested orally. It was discontinued from distribution by its parent company AstraZeneca in 2006 as it was found to raise liver enzyme levels in patients and cause liver damage as a result. Ximelagatran inhibits prothrombin. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is inhibited by ximelagatran, and is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V and ximelagatran inhibits prothrombin. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced and inhibited by ximelagatran, which then uses fibrinogen alphabet, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa. Prothrombin is inhibited by ximelagatran here as well. From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.

Ximelagatran is an anti-coagulant thrombin inhibitor that binds reversibly to the catalytic site and anion-binding exosite inhibiting the cleavage of fibrinogen into fibrin. Ximelagatran is used to treat heparin-induced thrombocytopenia as well as to prevent thrombosis. It is used in patients that are undergoing percutaneous coronary intervention or who have a risk in acute coronary syndromes caused by unstable angina or non-ST segment elevation. Thrombin is an important proteinase as it cleaves fibrinogen into fibrin monomers which help form the thrombus that forms the clot at the site of vascular injury. Because ximelagatran inhibits thrombin, clotting cannot form which is ideal for heart surgeries and some heart conditions. Ximelagatran should be monitored as it inhibits clotting so other injuries won't clot and it also can cause blood stagnation. Monitoring changes in hematocrit and blood pressure is extremely important when taking this drug. It is normally administered intravenously so that it is delivered to the site of action right away and can be controlled more easily. Ximelagatran is an anticoagulant drug used to prevent and treat blood clots, and was the first drug in the anticoagulant drug class to be able to be ingested orally. It was discontinued from distribution by its parent company AstraZeneca in 2006 as it was found to raise liver enzyme levels in patients and cause liver damage as a result.

Metabolites of Ximelagatran are predicted with biotransformer.

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Xylene is a common aromatic hydrocarbon used in the medical industry as a solvent. This pathway describes a part of how xylene is degraded in certain bacterial species. Xylene exists in different percentages in a laboratory-grade level and is of a few common kinds: m-xylene (40–65%), p-xylene (20%), o-xylene (20%) and ethylbenzene (6-20%) and traces of toluene, trimethyl benzene, phenol, thiophene, pyridine, and hydrogen sulfide. In the bigger picture of this pathway, m-xylene, p-xylene, o-xylene as well as toluene are considered, where part of the degradation processes for each of these xylene types have been illustrated. All degradation reactions here are taking place in the cytoplasm. One part of this pathway starts with 4-methylbenzoic acid / p-methylbenzoate which is a product downstream of the p-xylene degradation and forms other intermediates: cis-1,2-dihydroxy-4-methylcyclohexa-3,5-diene-1-carboxylate, 4-methylcatechol, 3-methyl-cis,cis-muconate, 4-methylmuconolactone and 3-methylmuconolactone aided by the proteins and protein complexes: toluate-1,2-deoxygenase alpha and beta subunit, cis-1,2-dihydroxycyclohexa-3,4-diene carboxylate dehydrogenase, catechol 1,2-dioxygenase, and muconate cycloisomerase I. It must be noted that the intermediate 3-methyl-cis,cis-muconate gives rise to two products in this pathway via two different reactions using the same protein muconate cycloisomerase I. The other section of this pathway demonstrates the degradation of o-methylbenzoate and m-methylbenzoate. o-Methylbenzoae degrades down to the intermediate 1,2-dihydroxy-6-methylcyclohexa-3,5-dienecarboxylate and m-methylbenzoate degrades down to the intermediate 1,2-dihydroxy-3-methylcyclohexa-3,5-dienecarboxylate. They both then degrade to the same product/intermediate 3-methylcatechol. These reactions are both catalyzed by the proteins probable ring-hydroxylating dioxygenase subunit and cis-1,2-dihydroxycyclohexa-3,4-diene carboxylate dehydrogenase respectively.

The degradation of xylose begins with NADP dependent trifunctional aldehyde reductase/xylose reductase/glucose 1-dehydrogenase resulting in the release of a NADPH, hydrogen ion and Xylitol. Xylitol reacts with a NAD D-xylulose reductase resulting in the release of NADH, a hydrogen ion and D-xylulose. Xylulose reacts with ATP through a xylulose kinase resulting in a release of ADP, hydrogen ion and xylulose 5-phosphate. The latter compound, xylulose 5-phosphate through a Ribulose-phosphate 3-epimerase resulting in the release of D-ribulose 5-phosphate. D-ribulose 5-phosphate and xylulose 5-phosphate react with a transketolase resulting in the release of D-glyceraldehyde 3-phosphate and D-sedoheptulose 7-phosphate. These two compounds react through a transaldolase resulting in the release of a D-erythrose 4-phosphate and Beta-D-fructofuranose 6-phosphate. D-erythrose 4-phosphate reacts with a xylulose 5-phosphate through a transketolase resulting in the release of Beta-D-fructofuranose 6-phosphate and D-glyceraldehyde 3-phosphate