Pathways

Amylase enzymes secreted in saliva by the parotid gland and in the small intestine play an important role in initiating starch digestion. The products of starch digestion are but not limited to maltotriose, maltose, limit dextrin, and glucose. The action of enterocytes of the small intestine microvilli further break down limit dextrins and disaccharides into monosaccharides: glucose, galactose, and fructose. Once released from starch or once ingested, sucrose can be degraded into beta-D-fructose and alpha-D-glucose via lysosomal alpha-glucosidase or sucrose-isomaltase. Beta-D-fructose can be converted to beta-D-fructose-6-phosphate by glucokinase and then to alpha-D-glucose-6-phosphate by the action of glucose phosphate isomerase. Phosphoglucomutase 1 can then act on alpha-D-glucose-6-phosphate (G6P) to generate alpha-D-glucose-1-phosphate. Alpha-D-glucose-1-phosphate (G6P) has several possible fates. It can enter into gluconeogenesis, glycolysis or the nucleotide sugar metabolism pathway. UDP-glucose pyrophosphorylase 2 can convert alpha-D-glucose-1-phosphate into UDP-glucose, which can then be converted to UDP-xylose or UDP-glucuronate and, eventually to glucuronate. UDP-glucose can also serve as a precursor to the synthesis of glycogen via glycogen synthase. Glycogen is an analogue of amylopectin (“plant starch”) and acts as a secondary short-term energy storage for animal cells. It’s formed primarily in liver and muscle tissues, but is also formed at secondary sites such as the central nervous system and the stomach. In both cases it exists as free granules in the cytosol. Glycogen is a crucial element of the glucose cycle as another enzyme, glycogen phosphorylase, cleaves off glycogen from the nonreducing ends of a chain to producer glucose-1-phosphate monomers. From there, the glucose-1-phosphate monomers have three possible fates: (1) enter the glycolysis pathway as glucose-6—phosphate (G6P) to generate energy, (2) enter the pentose phosphate pathway to produce NADPH and pentose sugar, or (3) enter the gluconeogenesis pathway by being dephosphorylated into glucose in liver or kidney tissues. To initiate the process of glycogen chain-lengthening, glycogenin is required because glycogen synthase can only add to existing chains. This action is subsequently followed by the action of glycogen synthase which catalyzes the formation of polymers of UDP-glucose connected by (α1→4) glycosidic bonds to form a glycogen chain. Importantly, amylo (α1→4) to (α1→6) transglycosylase catalyzes glycogen branch formation via the transfer of 6-7 glucose residues from a nonreducing end with greater than 11 residues to the C-6 OH- group in the interior of a glycogen molecule.

Carbohydrates are a major component of the diet, and include starch (amylose and amylopectin) and disaccharides such as sucrose, lactose, maltose and, in small amounts, trehalose. Once released from starch or once ingested, sucrose can be degraded into beta-D-fructose and alpha-D-glucose via lysosomal alpha-glucosidase or sucrose-isomaltase. Beta-D-Fructose can be converted to beta-D-fructose-6-phosphate by glucokinase and then to alpha-D-glucose-6-phosphate by the action of glucose phosphate isomerase. Phosphoglucomutase 1 can then act on alpha-D-glucose-6-phosphate (G6P) to generate alpha-D-glucose-1-phosphate. alpha-D-Glucose-1-phosphate (G6P) has several possible fates. It can enter into gluconeogenesis, glycolysis, or the nucleotide sugar metabolism pathway. UDP-glucose pyrophosphorylase 2 can convert alpha-D-glucose-1-phosphate into UDP-glucose, UDP-glucose can then be used to produce D-glucose via trehalose. UDP-glucose can also serve as a precursor to the synthesis of glycogen via glycogen synthase. Glycogen is a starch analogue commonly called an animal starch. Glycogen is found in the cytosol in granules. Glycogen is cleaved and converted to glucose-6-phosphate (G6P) which undergoes glycolysis or can enter the pentose phosphate pathway.

The STAT3 signalling pathway is a pathway activated by many different cytokines. It has also been found to be activated by many carcinogens. Cytokines are small proteins. These proteins are released by some of the cells in the immune system, and are vital to signalling pathways in the body of mammals. STAT3 is very important in the activation of the expression of certain mediators in the liver. STAT3 binds at the phosphotyrosine receptor which in turn phosphorylates tyrosine 705 at the C-terminal domain of STAT3, activating STAT3. If a receptor is missing tyrosine-kinase activity it will find tyrosine-kinases that are associated to the receptor, including JAK and Src when it is time for ligand engagement. Thanks to this recruitment, STAT3 is phosphorylated through the tyrosine phosphorylation cascade. This means that STAT3 is now activated, and its compounds disconnect from the receptor site, and relocate to the nucleus. Once there, the compounds bind to DNA response elements, and take part in many processes against target genes, such as apoptosis and cell proliferation, regulating their transcription.

The STAT3 signalling pathway is a pathway activated by many different cytokines. It has also been found to be activated by many carcinogens. Cytokines are small proteins. These proteins are released by some of the cells in the immune system, and are vital to signalling pathways in the body of mammals. STAT3 is very important in the activation of the expression of certain mediators in the liver. STAT3 binds at the phosphotyrosine receptor which in turn phosphorylates tyrosine 705 at the C-terminal domain of STAT3, activating STAT3. If a receptor is missing tyrosine-kinase activity it will find tyrosine-kinases that are associated to the receptor, including JAK and Src when it is time for ligand engagement. Thanks to this recruitment, STAT3 is phosphorylated through the tyrosine phosphorylation cascade. This means that STAT3 is now activated, and its compounds disconnect from the receptor site, and relocate to the nucleus. Once there, the compounds bind to DNA response elements, and take part in many processes against target genes, such as apoptosis and cell proliferation, regulating their transcription.

The STAT3 signalling pathway is a pathway activated by many different cytokines. It has also been found to be activated by many carcinogens. Cytokines are small proteins. These proteins are released by some of the cells in the immune system, and are vital to signalling pathways in the body of mammals. STAT3 is very important in the activation of the expression of certain mediators in the liver. STAT3 binds at the phosphotyrosine receptor which in turn phosphorylates tyrosine 705 at the C-terminal domain of STAT3, activating STAT3. If a receptor is missing tyrosine-kinase activity it will find tyrosine-kinases that are associated to the receptor, including JAK and Src when it is time for ligand engagement. Thanks to this recruitment, STAT3 is phosphorylated through the tyrosine phosphorylation cascade. This means that STAT3 is now activated, and its compounds disconnect from the receptor site, and relocate to the nucleus. Once there, the compounds bind to DNA response elements, and take part in many processes against target genes, such as apoptosis and cell proliferation, regulating their transcription.

The STAT3 signalling pathway is a pathway activated by many different cytokines. It has also been found to be activated by many carcinogens. Cytokines are small proteins. These proteins are released by some of the cells in the immune system, and are vital to signalling pathways in the body of mammals. STAT3 is very important in the activation of the expression of certain mediators in the liver. STAT3 binds at the phosphotyrosine receptor which in turn phosphorylates tyrosine 705 at the C-terminal domain of STAT3, activating STAT3. If a receptor is missing tyrosine-kinase activity it will find tyrosine-kinases that are associated to the receptor, including JAK and Src when it is time for ligand engagement. Thanks to this recruitment, STAT3 is phosphorylated through the tyrosine phosphorylation cascade. This means that STAT3 is now activated, and its compounds disconnect from the receptor site, and relocate to the nucleus. Once there, the compounds bind to DNA response elements, and take part in many processes against target genes, such as apoptosis and cell proliferation, regulating their transcription.

Acquired immunodeficiancy syndrome (AIDS) is generally accepted to be a consequence of infection with the retrovirus designated as human immunodeficiency virus (HIV-l). Stavudine is a potent and selective inhibitor of HIV-replication and of cytopathic effects in a variety of mammalian cells, and is relatively non-toxic to the uninfected human T-cell line H9. Stavudine, phosphorylates cellular enzymes to the mono-, di-, and triphosphates and is ultimately incorporated into the DNA of growing cells. A significant amount of radioactivity appears in the alkaline labile fraction of cells which are treated with Stavudine, due to terminal addition of Stavudine to DNA and the resultant chain termination.

Stavudine is a dideoxynucleoside used in the treatment of HIV infection. When HIV infects a cell, the virus first binds and fuses with the cell, releasing its nucleocapsid containing its RNA and reverse transcriptase into the cytosol of the cell. The reverse transcriptase converts the viral RNA into viral DNA in the cytosol. The viral DNA goes to the nucleus through the nuclear pore complex where it undergoes the process of transcription. The new viral RNA formed from transcription is transported back to the cytosol through the nuclear pore complex and translation occurs to produce viral proteins. These viral proteins are assembled and new HIV viruses bud from the cell. Stavudine enters the cell and is converted into stavudine monophosphate by thymidine kinase. Thymidylate kinase then converts stavudine monophosphate into stavudine diphosphate. Stavudine diphosphate is metabolized to stavudine triphosphate via nucleoside diphosphate kinase. Stavudine triphosphate is an analog of deoxyguanosine-5'-triphosphate (dGTP). Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its substrate, dGTP and by incorporation into viral DNA. Stavudine triphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once stavudine triphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed.

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