Pathways

Stiripentol is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Stiripentol passes through the liver and is then excreted from the body mainly through the kidney.

Stiripentol is an antiepileptic agent used in combination with other anticonvulsants to treat seizures associated with Dravet syndrome. Stiripentol is an antiepileptic agent that is an aromatic allylic alcohol drug, which makes it structurally unique from other antiepileptic drugs. The clinical development and marketing of stiripentol were first delayed due to the drug's potent inhibitory effects on hepatic cytochrome P450 (CYP) enzymes. However, its clinical efficacy as adjunctive therapy for epilepsies stems from its inhibitory action on CYP enzymes, as stiripentol reduces the degradation of CYP-sensitive antiepileptic drugs, hence boosting their therapeutic efficacy. The mechanism by which stiripentol exerts its anticonvulsant effect in humans has not been fully elucidated. Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid GABAA receptor and indirect effects involving inhibition of cytochrome P450 activity. Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs' metabolism and increasing blood plasma levels. Stiripentol is a positive allosteric modulator of GABAA receptors in the brain that enhances the opening duration of the channel by binding to a site different than the benzodiazepine binding site. It binds to GABAA receptors containing any of the α, β, γ, or δ-subunits but displays the most potent potency when bound to receptors containing α3 or δ subunits. Stiripentol also binds to GABAA receptor-dependent chloride channels via a barbiturate-like mechanism. Stiripentol potentiates GABA transmission by enhancing the release of GABA, reducing synaptosomal uptake of GABA, and inhibiting GABA transaminase-mediated breakdown of GABA. It can be found under the brand name Diatomite and can cause side effects such as tiredness, shaking, coordination issues, and nausea. Stiripentol is administered as an oral tablet.

Streptokinase, or SK, is an enzyme and also a thrombolytic medication. We are focusing on the medication in this pathway, which is used to dissolve clots in patients experiencing heart attacks, or arterial/pulmonary embolisms. Streptokinase works through enabling cleavage of the Arg/Val bond in plasminogen, so that plasmin is formed which breaks down fibrin matrix in the thrombus which in turn creates thrombolytic action. Streptokinase 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 through plasminogen, which is activated by streptokinase 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.

Streptokinase is a bacterial protein that is fibrinolytic and used to break down blood clots in myocardial infarction, pulmonary embolism and venous thromboembolism. It is administered intravenously and travels through the bloodstream to target blood clots. Streptokinase does this by converting plasminogen to its active form plasmin, by cleaving an arginine-valine bond. Once plasmin is activated it breaks down the fibrin mesh of the blood clot turning it into degradation products. Due to the anticoagulant and antiplatelet activity, herbs and supplements with a similar activity should be avoided such as garlic, ginger, bilberry, danshen, piracetam and ginkgo biloba.

Streptomycin (also named Gerox or Agrimycin) is an aminoglycoside antibiotic for the treatment of bacteria infections by inhibiting the synthesis of bacterial proteins. Streptomycin reversibly binds to 16S rRNA and the bacterial 30S ribosomal subunit so that the initiation complex with mRNA couldn't be formed. Binding of streptomycin on 16S rRNA's four nocleotides will lead to misreading of mRNA which result in insertion of incorrect amino acids into polypeptide. Nonfunctional or toxic peptides will lead to nonfunctional monosomes. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with penicillin-related antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Streptomycin is an antibiotic that treats multi-drug-resistant bacterial strains. It is in the aminoglycosides family and it is derived from Streptomyces griseus which was the first effective antibiotic against Mycobacterium tuberculosis. It is now largely a second-line option due to the development of resistance and toxicity. Streptomycin goes through 3 phases in order to infiltrate the bacterial cell and inhibit protein synthesis: the first phase is the binding of polycationic drug to the negatively charged bacterial cell membrane which increases membrane permeability. The second phase is the entry of aminoglycoside through oxygen-dependent active transport into the cell where it then travels and binds to the 16rRNA and 30S ribosomal subunit. The final phase is the inhibition of protein synthesis and the accumulation of Streptomycin in the cell which further exacerbates its inhibition of protein synthesis, elongation, and ribosome recycling. It is mainly used in combination with other antibiotics. It is commonly administered via intramuscular injection or intravenously and is eliminated in the urine 24 hours after its administration into the body. Some caution must be taken with streptomycin as overdose can lead to nephrotoxicity and ototoxicity.

Streptomycin, an antibiotic discovered in 1943, belongs to a class of drugs called aminoglycoside antibiotics. It is produced by Streptomyces griseus, a soil residing bacteria, and its role is to inhibit translation by interfering with the growth of the bacteria by inducing prokaryotic ribosomes to misread mRNA. This pathway shows the biosynthesis of streptomycin in a bacterial cell of Streptomyces griseus originating from a D-glucose compound. There are three branches to this pathway that give rise to the functional unit monomers: streptidine 6-phosphate, dTDP-L-dihydrostreptose and NDP-N-methyl-L-glucosamine, that streptomycin is made up of. The first branch on the left is involved in the eventual synthesis of the streptidine 6-phosphate intermediate which in this pathway has been shortened to show an intermediate upstream of it: amidino-scyllo-inosamine-4P synthesized via the protein scyllo-inosamine-4-phosphate amidinotransferase. The second branch in the center is involved in the synthesis of the monomer dTDP-L-dihydrostreptose synthesized via the protein putative dTDP-4-dehydrorhamnose 3,5-epimerase. The third branch on the right is involved in the synthesis of the monomer NDP-N-methyl-L-glucosamine from glucose-1-phosphate and no protein is involved in this reaction. The intermediates/monomeric units streptidine 6-phosphate and dTDP-L-dihydrostreptose are then involved in a reaction catalyzed by the protein putative dTDP-dihydrostreptose--streptidine-6-phosphate dihydrostreptosyltransferase to give rise to the intermediate O-(1->4)-alpha-L-dihydrostreptosyl-streptidine 6-phosphate and dTDP. O-(1->4)-alpha-L-dihydrostreptosyl-streptidine 6-phosphate along with NDP-N-methyl-L-glucosamine give rise to dihydrostreptomycin-6P and nucleoside diphosphate. Dihydrostreptomycin-6P reacts to form streptidine 6-phosphate again which reacts in a cyclic manner to form streptomycin. Streptomycin is then exported out of the cell to then be extracted as a useful antibiotic.

Streptozocin is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Streptozocin passes through the liver and is then excreted from the body mainly through the kidney.