Pathways

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.

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.

The steroid biosynthesis pathway occurs in the endoplasmic reticulum leads to the production of various sterols. In Arabidopsis thaliana, the major products are cholesterol, brassicasterol, stigmasterol, campesterol, and their derivatives. These products serve various roles including signalling and structural support. Stigmasterol is the principal sterol in with campesterol being second most abundant. The pathway begins with farnesyl pyrophosphate produced in the terpenoid backbone biosynthesis pathway. Squalene synthase catalyzes the reaction of two molecules of farnesyl pyrophosphate to form presqualene diphosphate and then squalene. Squalene is reduced by squalene monoxygenase to form 2,3-epoxysqualene. 2,3-epoxysqualene can be used to form cycloartenol via cycloartenol synthase. This leads to the primary path of steroid biosynthesis in Arabidopsis thaliana. Cycloartenol undergoes a series of reactions to form 24-methylenelophenol. 24-methylenelophenol can be converted to 24-ethylidenelophenol by 24-methylenesterol C-methyltransferase. 24-methylenelophenol and 24-ethylidenelophenol undergo similar separate reactions to form two different sterols. 24-methylenelophenol and 24-ethylidenelophenol are reduced by methylsterol monooxygenase 2 to episterol and δ7-avenasterol respectively. These are oxidized by delta(7)-sterol-C5(6)-desaturase to 5-dehydroepisterol and 5-dehydroavenasterol. These then undergo a series of reductions to form 24-methylenecholesterol and avenasterol; 24-epi-campesterol and β-sitosterol; and finally brassicasterol and stigmasterol. 24-methylenecholesterol may also be reduced by delta(24)-sterol reductase to form campesterol. Alternatively, lanosterol synthase can use 2,3-epoxysqualene to form lanosterol. Lanosterol is reduced by sterol-14-demethylase to form 4,4-dimethylcholesta-8,14,24-trienol and then by delta(14)-sterol reductase to form 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol. 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol then undergoes a series of reactions to for zymosterol. Zymosterol is converted into 5a-Cholest-8-en-3b-ol by delta(24)-sterol reductase, which is converted into lathosterol by 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase, then into 7-dehydrocholesterol by 7-dehydrocholesterol reductase, then into cholesterol by 7-dehydrocholesterol reductase.

The biosynthesis of steroids begins with acetyl coa being turned into acetoacetyl through a acetoacetyl CoA thiolase. Acetoacetyl -CoA reacts with an acetyl-CoA and water through a 3-hydroxy 3-methylglutaryl coenzyme A synthase resulting in the release of coenzyme A, hydrogen ion and (S)-3-hydroxy-3-methylglutaryl-CoA. The latter compound reacts with NADPH and a hydrogen ion through a 3-hydroxy-3-methylglutaryl-coenzyme A resulting in the release of coenzyme A , NADP and mevalonate. Mevalonate is then phosphorylated through an ATP driven kinase mevalonate kinase resulting in the release of ADP, hydrogen ion and mevalonate 5-phosphate. The latter compound is phosphorylated through an ATP driven kinase, phosphomevalonate kinase resulting in the release of ADP and mevalonate diphosphate. This latter compound then reacts with an ATP driven mevalonate diphosphate decarboxylase resulting in the release of ADP, carbon dioxide, a phosphate and a isopentenyl diphosphate. The latter compound can be isomerized into dimethylallyl diphosphate or reacth with a dimethylallyl diphosphate to produce geranyl diphosphate. Geranyl diphosphate reacts with a isopentenyl through a farnesyl diphosphate synthase resulting in the release of diphosphate and farnesyl diphosphate. The latter compound reacts with hydrogen ion, NADPH through a squalene synthetase resulting in the release NADP, pyrophosphate and squalene. The latter compound reacts with hydrogen ion NADPH and oxygen through squalene monooxygenase resulting in the release of NADP, Water and (3S)-2,3-epoxy-2,3-dihydrosqualene. The latter compound reacts through a 2,3-oxidosqualene lanosterol cyclase resulting in the release of lanosterol. Lanosterol reacts with hydrogen ion, NADPH, and oxygen through a cytochrome P450 lanosterol 14a demethylase resulting in the release of formate, water, NADP and 14-demethyllanosterol. The latter compound reacts with hydrogen ion and NADPH through a c-14 sterol reductase resulting in the release of NADP and 4,4-dimethylzymosterol. The latter compound reacts with methylsterol monooxygenase resulting in the release of 4α-hydroxymethyl-4β-methyl-5α-cholesta-8,24-dien-3β-ol which reacts with methylsterol monooxygenase twice to obtain 4α-carboxy-4β-methyl-5α-cholesta-8,24-dien-3β-ol. The latter compound then reacts with an NADP C-3 sterol dehydrogenase resulting in the release of water, NADP and 3-dehydro-4-methylzymosterol. The latter compound then reacts with NADPH and a hydrogen ion through a 3-keto sterol reductase resulting in the release of NADP and 4alpha-methyl-zymosterol. The latter compound then reacts with a methylsterol monooxygenase 3 times, followed by one reaction with c-sterol dehydrogenase and one reaction with 3-keto sterol reductase resulting in the release of a zymosterol. The latter compound reacts with SAM through a sterol methyltransferase resulting in the release of s-adenosylhomocysteine and fecosterol. Fecosterol is isomerized into episterol. The latter compound reacts with c-5 sterol desaturase resulting in the release of ergosta-5,7,24(28)-trien-3β-ol which then reacts with a c-22 sterol desaturase resulting in the release of ergosta-5,7,22,24(28)-tetraen-3-β-ol. This latter compound then reacts with a C-24 sterol reductase resulting in the release of an ergosterol.