Pathways

Metabolites of Metronidazole are predicted with biotransformer.

The mevalonate pathway, also known as the isoprenoid pathway, plays an essential role in creating the chemicals needed for many plants to function. This pathway, combined with the MEP/DOXP pathway give many plants their scents, such as cinnamon and ginger, and are responsible for the red colour in tomatoes. The pathway begins with acetyl-CoA, having come from the glycolysis pathway. Acetyl-CoA immediately becomes acetoacetyl-CoA through the enzyme acetyl-CoA acetyltransferase 1/2. Combined, acetoacetyl-CoA and acetyl-CoA react with hydroxymethylglutaryl-CoA synthase to create 3-hydroxy-3methylglutaryl-CoA. From here, this compound is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 and becomes (R)-mevalonate. Mevalonate is paired with mevalonate kinase to produce mevalonic acid-5P. In turn, mevalonic acid-5P reacts with phosphomevalonate kinase, and entering the peroxisome and becoming (R)-mevalonic acid-5-pyrophosphate. Remaining in the peroxisome, diphosphomevalonate decarboxylase MVD1 is used alongside (R)-mevalonic acid-5-pyrophosphate to create isopentenyl pyrophosphate, bringing the pathway into the chloroplast. Dimethylallylpyrophosphate is produced after isopentenyl pyrophosphate and isopentenyl diphosphate delta-isomerase II team up to catalyze it. Dimethylallylpyrophosphate then joins forces with isopentenyl again, this time adding geranylgeranyl pyrophosphate synthase 6 and moving into the mitochondria to produce geranyl-PP. This is followed by monoterpenoid biosynthesis.

The Mevalonate Pathway is a necessary pathway that occurs in archaea, eukaryotes and select bacteria. It has mainly been studied with regard to cholesterol biosynthesis and how it relates to cardiovascular disease in humans, but has recently garnered attention for its many other essential roles within human pathology. The pathway begins in the cytoplasm with acetyl-CoA and acetoacetyl-CoA, which interact with acetyl-CoA acetyltransferase, coenzyme A and water to synthesize hydroxymethylglutaryl-CoA synthase. In turn, this synthase teams up with coenzyme A and a hydrogen ion in the endoplasmic reticulum to create 3-hydroxy-3-methylglutaryl-CoA. 3-Hydroxy-3-methylglutaryl-CoA then pairs with 2NADPH, 2 hydrogen ions and is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase to produce (R)-mevalonate, also producing byproducts CoA and NADP. Exiting the endoplasmic reticulum, and entering the peroxisome, (R)-mevalonate uses the help of ATP and mevalonate kinase to create mevalonic acid (5P). This piece is especially important to the human species as decreased activity of the enzyme mevalonate kinase has been found to be a direct link to two auto-inflammatory disorders: MVA and HIDS. Using phosphomevalonate kinase and ATP, the pathway re-enters the cytoplasm and mevalonic acid (5P) converts to (R)-mevalonic acid-5-pyrophosphate and ADP. (R)-mevalonic acid-5-pyrophosphate, ATP and diphosphomevalonate decarboxylase work together to create phosphate, carbon dioxide, ADP and isopentenyl pyrophosphate. Re-entering the peroxisome, isopentenyl diphosphate delta isomerase 1 is waiting to propel isopentenyl pyrophosphate into dimethylallylpyrophosphate. This pushes the pathway back into the cytoplasm, where another isopentenyl pyrophosphate molecule and the enzyme farnesyl pyrophosphate synthase create pyrophosphate and geranyl-PP. Yet another isopentenyl pyrophosphate molecules works with farnesyl pyrophosphate synthase to produce pyrophosphate and farnesyl pyrophosphate. Now in the endoplasmic reticulum membrane, 2 farnesyl pyrophosphate molecules with the help of NADPH and a hydrogen ion catalyze with squalene synthase and create squalene. This is an important first step in the specific hepatic cholesterol pathway. Remaining in the endoplasmic reticulum membrane, squalene, FMNH, oxygen and squalene monooxygenase synthesize (S)-2,3-epoxysqualene. This comes along with the byproducts of flavin mononucleotide, a hydrogen ion and water. In the final reaction within this pathway, lanesterol synthase converts (S)-2,3-epoxysqualene to lanosterin. Not pictured in this pathway, lanosterin will eventually be converted to cholesterol, an important part of many functions in the human body.

The mevalonate pathway, also known as the isoprenoid pathway, plays an essential role in creating the chemicals needed for many plants to function. This pathway, combined with the MEP/DOXP pathway give many plants their scents, such as cinnamon and ginger, and are responsible for the red colour in tomatoes. The pathway begins with acetyl-CoA, having come from the glycolysis pathway. Acetyl-CoA immediately becomes acetoacetyl-CoA through the enzyme acetyl-CoA acetyltransferase 1/2. Combined, acetoacetyl-CoA and acetyl-CoA react with hydroxymethylglutaryl-CoA synthase to create 3-hydroxy-3methylglutaryl-CoA. From here, this compound is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 and becomes (R)-mevalonate. Mevalonate is paired with mevalonate kinase to produce mevalonic acid-5P. In turn, mevalonic acid-5P reacts with phosphomevalonate kinase, and entering the peroxisome and becoming (R)-mevalonic acid-5-pyrophosphate. Remaining in the peroxisome, diphosphomevalonate decarboxylase MVD1 is used alongside (R)-mevalonic acid-5-pyrophosphate to create isopentenyl pyrophosphate, bringing the pathway into the chloroplast. Dimethylallylpyrophosphate is produced after isopentenyl pyrophosphate and isopentenyl diphosphate delta-isomerase II team up to catalyze it. Dimethylallylpyrophosphate then joins forces with isopentenyl again, this time adding geranylgeranyl pyrophosphate synthase 6 and moving into the mitochondria to produce geranyl-PP. This is followed by monoterpenoid biosynthesis.

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).