Pathways

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

Thio-molybdenum cofactor biosynthesis is a pathway that begins in the mitochondrial matrix and ends in the cytosol by which GTP becomes thio-molybdenum cofactor, the sulfo-form of molybdenum cofactor required by certain plant enzymes. First, the enzyme GTP 3',8-cyclase, located in the mitochondrial matrix, catalyzes the conversion of GTP, S-adenosylmethionine, and a reduced electron acceptor to 3′,8-cH2GTP, L-methionine, 5'-deoxyadenosine, an oxidized electron acceptor, and a hydrogen ion with the help of a [4Fe-4S] cluster cofactor. Second, cyclic pyranopterin monophosphate (cPMP) synthase catalyzes the conversion of 3′,8-cH2GTP to cPMP and pyrophosphate. Next, ABC transporter of the mitochondrion 3 (ATM3) exports cPMP from the mitochondrial matrix into the cytosol where it is acted upon by molybdopterin (MPT) synthase. MPT synthase is a heterotetramer composed of 2 large and 2 small subunits. The two small subunits are thiocarboxylated by molydopterin synthase sulfurtransferase, and each transfers a sulfur to cPMP to generate the dithiolene in molybdopterin and releasing hydrogen ion in the process. The following enzyme in the pathway, molybdenum insertase is a two-domain protein that catalyzes the fourth and fifth reactions. The smaller C-terminal Cnx1G domain functions as a molybdopterin molybdotransferase and activates molybdopterin for molybdenum insertion. The product of this reaction, molybdopterin adenine dinucleotide (MPT-AMP), is then transferred to the larger N-terminal Cnx1E domain which exhibits molybdopterin adenylyltransferase activity and inserts molybdenum into the dithiolene of molybdopterin, creating molybdenum cofactor (Moco). Molybdenum insertase requires a divalent cation (e.g. magnesium) as a cofactor. Lastly, molybdenum cofactor sulfurtransferase uses L-cysteine and a reduced electron acceptor to convert molybdenum cofactor into thio-molybdenum cofactor, producing L-alanine, oxidized electron acceptor, and water as byproducts. It requires pyridoxal 5'-phosphate as a cofactor.

Thiocolchicoside is a semi-synthetic colchicine derivative used as skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders. It is indicated as an adjuvant drug in the treatment of painful muscle contractures and is indicated in acute spinal pathology, for adults and adolescents 16 years of age and older.thiocolchicoside binds on the benzodiazepine receptors in the post-synaptic GABA-A ligand-gated chloride channel in different sites of the central nervous system (CNS). This binding will result in an increase on the GABA inhibitory effects which is translated as an increase in the flow of chloride ions into the cell causing hyperpolarization and stabilization of the cellular plasma membrane. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics.

Thioguanine is an antineoplastic compound used to treat acute leukemia. It is usually administered orally and delivered to the site of action through the blood. Thioguanine has similar properties to 6-mercaptopurine as they share similar metabolites with the exception of 6-meraptopurine inhibiting the purine de novo synthesis pathway. Thioguanine's metabolites thiodeoxyguanosine-5'-triphosphate and thioguanosine 5'-triphosphate can be incorporated into DNA and RNA respectively which causes proliferation and protein synthesis to be inhibited. Thioguanosine 5'-triphosphate also inhibits ras-related C3 botulinum toxin substrate 1 a small GTPase membrane protein responsible for regulating cellular functions like cell growth, antimicrobial cytotoxicity, apoptosis regulation of lymphocytes. With ras-related C3 botulinum toxin substrate 1 being inhibited, apoptosis of T and B lymphocytes is no longer regulated and they are killed off. This leads to immunosuppression.

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.

Metabolites of sildenafil are predicted with biotransformer.