Pathways

Urokinase is a serine protease that functions as a recombinant tissue plasminogen activator. It is administered intravenously and used to treat conditions caused by arterial blood clots such as acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism and blocked central venous access devices. It targets plasminogen in blood vessels where these clots occur. The clotting process consists of two pathways, intrinsic and extrinsic, which converge to create stable fibrin which traps platelets and forms a hemostatic plug. The intrinsic pathway is activated by trauma inside the vasculature system, when there is exposed endothelial collagen. Endothelial collagen only becomes exposed when there is damage. The pathway starts with plasma kallikrein activating factor XII. The activated factor XIIa activates factor XI. Factor IX is then activated by factor XIa. Thrombin activates factor VIII and a Calicum-phospholipid-XIIa-VIIIa complex forms. This complex then activates factor X, the merging point of the two pathways. The extrinsic pathway is activated when external trauma causes blood to escape the vasculature system. Activation occurs through tissue factor released by endothelial cells after external damage. The tissue factor is a cellular receptor for factor VII. In the presence of calcium, the active site transitions and a TF-VIIa complex is formed. This complex aids in activation of factors IX and X. Factor V is activated by thrombin in the presence of calcium, then the activated factor Xa, in the presence of phospholipid, calcium and factor Va can convert prothrombin to thrombin. The extrinsic pathway occurs first, producing a small amount of thrombin, which then acts as a positive feedback on several components to increase the thrombin production. Thrombin converts fibrinogen to a loose, unstable fibrin and also activates factor XIII. Factors XIIIa strengthens the fibrin-fibrin and forms a stable, mesh fibrin which is essential for clot formation. The blood clot can be broken down by the enzyme plasmin. Plasmin is formed from plasminogen by tissue plasminogen activator. Urokinase acts as a tissue plasminogen activator. It binds to clots with fibrin where it causes hydrolysis of the arginine-valine bond in plasminogen, aiding its conversion to plasmin. The plasmin degrades the stable fibrin and causes lysis of the clot. The activity of Urokinase depends on the presence of fibrin. Only small amounts of plasmin is formed from plasminogen when there is no fibrin. Urokinase in the presence of fibrin obtains a higher affinity for plasminogen, thus leading to its increased activity. Urokinase undergoes metabolism by proteases and is excreted in bile and urine.

Urokinase is an enzyme that is part of the thrombolytics drug class, used to dissolve or break down blood clots. Urokinase activates plasminogen. 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 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. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, 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 (urokinase) 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. 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.

Metabolites of Valaciclovir are predicted with biotransformer.

Valaciclovir (valacyclovir), also known as the brand name Valtrex, is an guanine nucleoside antiviral used to treat herpes exacerbations. Valaciclovir is the L-valine ester of aciclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is transported from the liver into the blood via a drug transporter, then into the effected cells. Acyclovir is a guanosine analog used to treat herpes simplex, varicella zoster, herpes zoster, herpes labialis, and acute herpetic keratitis. Acyclovir is becomes acyclovir monophosphate due to the action of viral thymidine kinase.5 Acyclovir monophosphate is converted to the diphosphate form by guanylate kinase.1 Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase. Acyclovir triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Acyclovir triphosphate also gets incorporated into viral DNA, but since it lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, this causes DNA chain termination, preventing the growth of viral DNA. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.