Pathways

This pathway depicts the synthesis and breakdown of porphyrin. The porphyrin ring is the framework for the heme molecule, the pigment in hemoglobin and red blood cells. The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinyl-CoA by delta-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis, ALA is transported into the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane (also known as HMB). The enzyme that catalyzes this condensation is known as porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane (HMB) has two main fates. Most frequently it is enzymatically converted into uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by two enzymes: uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also be non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the uroporphyrinogens (uroporphyrinogen III or uroporphyrinogen I) are decarboxylated by the enzyme uroporphyrinogen decarboxylase. These new products have methyl groups in place of the original acetate groups and are known as coproporphyrinogens. Coproporphyrinogen III is the most important intermediate in heme synthesis. Coproporphyrinogen III is transported back from the cytosol into the interior of the mitochondria, where two propionate residues are decarboxylated (via coproporphyrinogen-III oxidase), which results in vinyl substituents on the 2 pyrrole rings. The resulting product is called protoporphyrinogen IX. The protoporphyrinogen IX is then converted into protoporphyrin IX by another enzyme called protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place within the mitochondria and involves the insertion of the iron atom into the ring system generating the molecule known heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The largest repository of heme in the body is in red blood cells (RBCs). RBCs have a life span of about 120 days. When the RBCs have reached the end of their useful lifespan, the cells are engulfed by macrophages and their constituents recycled or disposed of. Heme is broken down when the heme ring is opened by the enzyme known as heme oxygenase, which is found in the endoplasmic reticulum of the macrophages. The oxidation process produces the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). The carbon monoxide (which is toxic) is eventually discharged through the lungs. In the next reaction, a second methylene group (located between rings III and IV of the porphyrin ring) is reduced by the enzyme known as biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin. This reduction causes a change in the colour of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds two additional glucuronic acid molecules to bilirubin to produce the more water-soluble version of the molecule known as bilirubin diglucuronide. In most individuals, intestinal bilirubin is acted on by the gut bacteria to produce the final porphyrin products, urobilinogens and stercobilins. These are excreted in the feces. The stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces. Some of the urobilinogen produced by the gut bacteria is reabsorbed and re-enters the circulation. These urobilinogens are converted into urobilins that are then excreted in the urine which cause the yellowish colour in urine.

This pathway depicts the synthesis and breakdown of porphyrin. The porphyrin ring is the framework for the heme molecule, the pigment in hemoglobin and red blood cells. The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinyl-CoA by delta-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis, ALA is transported into the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane (also known as HMB). The enzyme that catalyzes this condensation is known as porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane (HMB) has two main fates. Most frequently it is enzymatically converted into uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by two enzymes: uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also be non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the uroporphyrinogens (uroporphyrinogen III or uroporphyrinogen I) are decarboxylated by the enzyme uroporphyrinogen decarboxylase. These new products have methyl groups in place of the original acetate groups and are known as coproporphyrinogens. Coproporphyrinogen III is the most important intermediate in heme synthesis. Coproporphyrinogen III is transported back from the cytosol into the interior of the mitochondria, where two propionate residues are decarboxylated (via coproporphyrinogen-III oxidase), which results in vinyl substituents on the 2 pyrrole rings. The resulting product is called protoporphyrinogen IX. The protoporphyrinogen IX is then converted into protoporphyrin IX by another enzyme called protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place within the mitochondria and involves the insertion of the iron atom into the ring system generating the molecule known heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The largest repository of heme in the body is in red blood cells (RBCs). RBCs have a life span of about 120 days. When the RBCs have reached the end of their useful lifespan, the cells are engulfed by macrophages and their constituents recycled or disposed of. Heme is broken down when the heme ring is opened by the enzyme known as heme oxygenase, which is found in the endoplasmic reticulum of the macrophages. The oxidation process produces the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). The carbon monoxide (which is toxic) is eventually discharged through the lungs. In the next reaction, a second methylene group (located between rings III and IV of the porphyrin ring) is reduced by the enzyme known as biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin. This reduction causes a change in the colour of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds two additional glucuronic acid molecules to bilirubin to produce the more water-soluble version of the molecule known as bilirubin diglucuronide. In most individuals, intestinal bilirubin is acted on by the gut bacteria to produce the final porphyrin products, urobilinogens and stercobilins. These are excreted in the feces. The stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces. Some of the urobilinogen produced by the gut bacteria is reabsorbed and re-enters the circulation. These urobilinogens are converted into urobilins that are then excreted in the urine which cause the yellowish colour in urine.

This pathway depicts the synthesis and breakdown of porphyrin. The porphyrin ring is the framework for the heme molecule, the pigment in hemoglobin and red blood cells. The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinyl-CoA by delta-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis, ALA is transported into the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane (also known as HMB). The enzyme that catalyzes this condensation is known as porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane (HMB) has two main fates. Most frequently it is enzymatically converted into uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by two enzymes: uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also be non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the uroporphyrinogens (uroporphyrinogen III or uroporphyrinogen I) are decarboxylated by the enzyme uroporphyrinogen decarboxylase. These new products have methyl groups in place of the original acetate groups and are known as coproporphyrinogens. Coproporphyrinogen III is the most important intermediate in heme synthesis. Coproporphyrinogen III is transported back from the cytosol into the interior of the mitochondria, where two propionate residues are decarboxylated (via coproporphyrinogen-III oxidase), which results in vinyl substituents on the 2 pyrrole rings. The resulting product is called protoporphyrinogen IX. The protoporphyrinogen IX is then converted into protoporphyrin IX by another enzyme called protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place within the mitochondria and involves the insertion of the iron atom into the ring system generating the molecule known heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The largest repository of heme in the body is in red blood cells (RBCs). RBCs have a life span of about 120 days. When the RBCs have reached the end of their useful lifespan, the cells are engulfed by macrophages and their constituents recycled or disposed of. Heme is broken down when the heme ring is opened by the enzyme known as heme oxygenase, which is found in the endoplasmic reticulum of the macrophages. The oxidation process produces the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). The carbon monoxide (which is toxic) is eventually discharged through the lungs. In the next reaction, a second methylene group (located between rings III and IV of the porphyrin ring) is reduced by the enzyme known as biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin. This reduction causes a change in the colour of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds two additional glucuronic acid molecules to bilirubin to produce the more water-soluble version of the molecule known as bilirubin diglucuronide. In most individuals, intestinal bilirubin is acted on by the gut bacteria to produce the final porphyrin products, urobilinogens and stercobilins. These are excreted in the feces. The stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces. Some of the urobilinogen produced by the gut bacteria is reabsorbed and re-enters the circulation. These urobilinogens are converted into urobilins that are then excreted in the urine which cause the yellowish colour in urine.

This pathway depicts the synthesis and breakdown of porphyrin. The porphyrin ring is the framework for the heme molecule, the pigment in hemoglobin and red blood cells. The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinyl-CoA by delta-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis, ALA is transported into the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane (also known as HMB). The enzyme that catalyzes this condensation is known as porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane (HMB) has two main fates. Most frequently it is enzymatically converted into uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by two enzymes: uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also be non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the uroporphyrinogens (uroporphyrinogen III or uroporphyrinogen I) are decarboxylated by the enzyme uroporphyrinogen decarboxylase. These new products have methyl groups in place of the original acetate groups and are known as coproporphyrinogens. Coproporphyrinogen III is the most important intermediate in heme synthesis. Coproporphyrinogen III is transported back from the cytosol into the interior of the mitochondria, where two propionate residues are decarboxylated (via coproporphyrinogen-III oxidase), which results in vinyl substituents on the 2 pyrrole rings. The resulting product is called protoporphyrinogen IX. The protoporphyrinogen IX is then converted into protoporphyrin IX by another enzyme called protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place within the mitochondria and involves the insertion of the iron atom into the ring system generating the molecule known heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The largest repository of heme in the body is in red blood cells (RBCs). RBCs have a life span of about 120 days. When the RBCs have reached the end of their useful lifespan, the cells are engulfed by macrophages and their constituents recycled or disposed of. Heme is broken down when the heme ring is opened by the enzyme known as heme oxygenase, which is found in the endoplasmic reticulum of the macrophages. The oxidation process produces the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). The carbon monoxide (which is toxic) is eventually discharged through the lungs. In the next reaction, a second methylene group (located between rings III and IV of the porphyrin ring) is reduced by the enzyme known as biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin. This reduction causes a change in the colour of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds two additional glucuronic acid molecules to bilirubin to produce the more water-soluble version of the molecule known as bilirubin diglucuronide. In most individuals, intestinal bilirubin is acted on by the gut bacteria to produce the final porphyrin products, urobilinogens and stercobilins. These are excreted in the feces. The stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces. Some of the urobilinogen produced by the gut bacteria is reabsorbed and re-enters the circulation. These urobilinogens are converted into urobilins that are then excreted in the urine which cause the yellowish colour in urine.

Porphyrins are organic compounds. Many porphyrins are involved in oxygen transportation. Porphyrin ring biosynthesis begins in the mitochondria and involves glycine and succinyl-CoA condensation by δ-aminolevulinic acid synthase (ALAS) to produce δ-aminolevulinic acid (ALA), also known as 5-aminolevulinic acid. ALA is then transported to the cytosol where it becomes dimerized by ALA dehydratase (also known as porphobilinogen synthase) to produce porphobilinogen. The pathway continues with the condensation of 4 molecules of porphobilinogen catalyzed by porphobilinogen deaminase (PBG deaminase, also called hydroxymethylbilane synthase or uroporphyrinogen I synthase) to produce hydroxymethylbilane. Hydroxymethylbilane may then be converted to uroporphyrinogen III, a heme intermediate, or it may be non-enzymatically cyclized to uroporphyrinogen I. In the cytosol, uroporphyrinogen I and III substituents become decarboxylated to become coproporphyrinogens. Coproporphyrinogen III is an important intermediate in the synthesis of heme. In the inner mitochondria, coproporphyrinogen III undergoes decarboxylation of 2 propionate residues producing protoporphyrinogen IX. Protoporphyrinogen IX oxidase converts protoporphyrinogen IX to protoporphyrin IX. The final reaction of heme synthesis is ferrochelatase catalyzing the insertion of iron into the ring, producing heme b. Heme is broken down when heme oxygenase opens the heme ring. This oxidation produces linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). Biliverdin reductase then produces bilirubin.

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action. Posaconazole binds to the enzyme lanosterol 14-alpha demethylase which inhibits the synthesis of 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol . Lanosterol 14-alpha demethylase is the enzyme that catalyzes the synthesis of 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol from lanosterol. With this enzyme inhibited ergosterol synthesis cannot occur which causes a significant low concentration of ergosterol in the fungal cell. Ergosterol is essential in maintaining membrane integrity in fungi. Without ergosterol, the fungus cell cannot synthesize membranes thereby increasing fluidity and preventing growth of new cells. This leads to cell lysis which causes it to collapse and die.

Metabolites of Posaconazole are predicted with biotransformer.

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