Pathways

The condition pyridoxine dependent-epilepsy is a condition that sees seizures beginning in infancy. In some cases, the seizures begin before birth. The seizures involve status epilepticus, which are seizures that last several minutes. The symptoms specific to pyridoxine dependent seizures can include hypothermia, dystonia and irritability right before an episode. They also include loss of consciousness, convulsions, and muscle rigidity. Rarely does this condition manifest between 1 to 3 years of age, although it has occured. Traditional anticonvulsant medication has proven ineffective in patients with this condition; patients are instead treated with pyridoxine daily in large doses. This compound is a b-vitamin found in food. Encephalopathy can occur if this condition is not treated, which can result in permanent brain damage. Although this condition is treated with pyridoxine, it can still cause neurological issues, such as learning disorders or developmental delay, regardless of treatment.

The condition pyridoxine dependent-epilepsy is a condition that sees seizures beginning in infancy. In some cases, the seizures begin before birth. The seizures involve status epilepticus, which are seizures that last several minutes. The symptoms specific to pyridoxine dependent seizures can include hypothermia, dystonia and irritability right before an episode. They also include loss of consciousness, convulsions, and muscle rigidity. Rarely does this condition manifest between 1 to 3 years of age, although it has occured. Traditional anticonvulsant medication has proven ineffective in patients with this condition; patients are instead treated with pyridoxine daily in large doses. This compound is a b-vitamin found in food. Encephalopathy can occur if this condition is not treated, which can result in permanent brain damage. Although this condition is treated with pyridoxine, it can still cause neurological issues, such as learning disorders or developmental delay, regardless of treatment.

The degradation of deoxycytidine starts with deoxycytidine being introduced into the cytosol through either a nupG or nupC symporter. Once inside, it can can be degrade through water,a hydrogen ion and a deoxycytidien deaminsa resultin in the release of a ammonium and a a deoxyuridine. The deoxyuridine is then degraded through a uracil phosphorylase resulting in the release of a deoxyribose 1-phosphate and a uracil. The degradation of thymidine starts with thymidine being introduced into the cytosol through either a nupG or nupC symporter. Thymidine is then degrades through a phosphorylase resulting in the release of a thymine and a deoxyribose 1-phosphate.

The cytosolic salvage of precursors used to synthesize pyrimidine deoxyribonucleotides from the environment is an important alternative to the energetically expensive de novo synthesis pathway. Since the negative charge of the deoxyribonucleotide phosphate groups prevents their import into the cell, salvage is restricted to deoxyribonucleosides which are transported into the cell via facilitated diffusion by a nucleoside carrier protein. Following uptake into the cell, the deoxyribonucleosides are phosphorylated. Phosphorylation imparts negative charges to the compounds, effectively trapping them within the cell. After transport into the cell, 2'-deoxycytidine has two fates. The first route starts with the conversion of 2'-deoxycytidine into dCMP by deoxynucleoside kinase. This is followed by the conversion of dCMP into dCDP by UMP/CMP kinase, requiring a magnesium ion cofactor, and then the conversion of dCDP into dCTP by nucleoside-diphosphate kinase, requiring a magnesium ion cofactor. The second route starts with the conversion of 2'-deoxycytidine into 2'-deoxyuridine by cytidine deaminase, requiring a zinc ion cofactor. This is followed by the conversion of 2'-deoxyuridine into dUMP by thymidine kinase, and then the conversion of dUMP into dTMP by dihydrofolate reductase-thymidylate synthase. Alternatively, dTMP can be synthesized by thymidine kinase using thymidine transported into the cell by a nucleoside carrier protein. Next, thymidylate kinase converts dTMP into dTDP, and then nucleoside-diphosphate kinase, requiring a magnesium ion cofactor, converts dTDP into dTTP.

A group of heterocyclic aromatic organic compound, pyrimidines are similar in structure to benzene and pyridine and count the nucleic acids cytosine, thymine, and uracil as structural derivatives. The following pathway illustrates a many pyrimidine-associated processes such as nucleotide biosynthesis, degradation, and salvage. This pathway depicts a number of pyrimidine-related processes such as nucleotide biosynthesis, degradation, and salvage. For pyrimidine nucleotide biosynthesis, carbamoyl phosphate derived from the action of carbamoyl phosphate synthetase II (CPS-II) on glutamine and bicarbonate is converted into carbamoyl aspartate by aspartate transcarbamoylase, ATCase. Dihydroorotic acid is subsequently generated by the action of carbamoyl aspartate dehydrogenase on carbamoyl aspartate. Dihydroorotate dehydrogenase then converts dihydroorotic acid to orotic acid. From this point, orotate phosphoribosyltransferase incorporates phosphoribosyl pyrophosphate into (PRPP) to produce orotidine monophosphate. Orotidine-5’-phosphate carboxylase subsequently converts orotidine monophosphate into uridine monophosphate (UMP). UMP is further phosphorylated twice to form UTP; the first instance by uridylate kinase and the second instance by ubiquitous nucleoside diphosphate kinase. UTP moves into the CTP synthesis pathway with the action of CTP synthase which aminates the molecule. The uridine nucleotides are also feedstock for the de novo thymine nucleotides synthesis pathway. DeoxyUMP which is derived from UDP or CDP metabolism is transformed by the action of thymidylate synthase into deoxyTMP of which the methyl group is sourced from N5,N10-methylene THF. THF is subsequently regenerated from DHF via dihydrofolate reductase (DHFR) which is essential for the continuation of thymidylate synthase activity. Serine hydroxymethyl transferase then acts on THF to regenerate N5,N10-THF. Pyrimidine synthesis is a comparatively simpler process than purine synthesis due to a couple of factors; pyrimidine ring structure is assembled as a free base rather being derived from PRPP and there is no branch in the pyrimidine synthesis pathway as opposed to the purine synthesis pathway. For thymidine, the action of thymidine kinase on it (or alternatively deoxyuridine) plays an important role in what is referred to as the salvage pathway to dTTP synthesis. However to form dTMP, the action of thymine phosphorylase and thymidine kinase is required. For deoxycytidine, deoxycytidine kinase is required (deoxycytidine also acts on deoxyadenosine and deoxyguanosine). For uracil, UMP can be formed by the action of uridine phosphorylase and uridine kinase on uracil. Pyrimidine catabolism ultimately results in the formation of the waste products of urea, H2O, and CO2. The product of cytosine breakdown, uracil, can be broken down to N-carbamoyl-β-alanine which can be catabolized into β-alanine. The product of thymine breakdown is β-aminoisobutyrate. The transamination of α-ketoglutarate to glutamate requires both of these breakdown products (β-alanine and β-aminoisobutyrate) to act as amine group donors. The products of this transamination can move through a further reaction that produces malonyl-CoA or methylmalonyl-CoA, a precursor for succinyl-CoA which is used in the Krebs cycle.

The metabolism of pyrimidines begins with L-glutamine interacting with water molecule and a hydrogen carbonate through an ATP driven carbamoyl phosphate synthetase resulting in a hydrogen ion, an ADP, a phosphate, an L-glutamic acid and a carbamoyl phosphate. The latter compound interacts with an L-aspartic acid through a aspartate transcarbamylase resulting in a phosphate, a hydrogen ion and a N-carbamoyl-L-aspartate. The latter compound interacts with a hydrogen ion through a dihydroorotase resulting in the release of a water molecule and a 4,5-dihydroorotic acid. This compound interacts with an ubiquinone-1 through a dihydroorotate dehydrogenase, type 2 resulting in a release of an ubiquinol-1 and an orotic acid. The orotic acid then interacts with a phosphoribosyl pyrophosphate through a orotate phosphoribosyltransferase resulting in a pyrophosphate and an orotidylic acid. The latter compound then interacts with a hydrogen ion through an orotidine-5 '-phosphate decarboxylase, resulting in an release of carbon dioxide and an Uridine 5' monophosphate. The Uridine 5' monophosphate process to get phosphorylated by an ATP driven UMP kinase resulting in the release of an ADP and an Uridine 5--diphosphate. Uridine 5-diphosphate can be metabolized in multiple ways in order to produce a Deoxyuridine triphosphate. 1.-Uridine 5-diphosphate interacts with a reduced thioredoxin through a ribonucleoside diphosphate reductase 1 resulting in the release of a water molecule and an oxidized thioredoxin and an dUDP. The dUDP is then phosphorylated by an ATP through a nucleoside diphosphate kinase resulting in the release of an ADP and a DeoxyUridine triphosphate. 2.-Uridine 5-diphosphate interacts with a reduced NrdH glutaredoxin-like protein through a Ribonucleoside-diphosphate reductase 1 resulting in a release of a water molecule, an oxidized NrdH glutaredoxin-like protein and a dUDP. The dUDP is then phosphorylated by an ATP through a nucleoside diphosphate kinase resulting in the release of an ADP and a DeoxyUridine triphosphate. 3.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate. The latter compound interacts with a reduced flavodoxin through ribonucleoside-triphosphate reductase resulting in the release of an oxidized flavodoxin, a water molecule and a Deoxyuridine triphosphate 4.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate interacts with a reduced flavodoxin through a ribonucleoside-triphosphate reductase resulting in the release of a water molecule, an oxidized flavodoxin and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate. 5.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate then interacts spontaneously with a water molecule resulting in the release of a phosphate, a hydrogen ion and a CDP. The CDP then interacts with a reduced NrdH glutaredoxin-like protein through a ribonucleoside-diphosphate reductase 2 resulting in the release of a water molecule, an oxidized NrdH glutaredoxin-like protein and a dCDP. The dCDP is then phosphorylated through an ATP driven nucleoside diphosphate kinase resulting in an ADP and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate. 6.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate then interacts spontaneously with a water molecule resulting in the release of a phosphate, a hydrogen ion and a CDP. The CDP interacts with a reduced thioredoxin through a ribonucleoside diphosphate reductase 1 resulting in a release of a water molecule, an oxidized thioredoxin and a dCDP. The dCDP is then phosphorylated through an ATP driven nucleoside diphosphate kinase resulting in an ADP and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate. The deoxyuridine triphosphate then interacts with a water molecule through a nucleoside triphosphate pyrophosphohydrolase resulting in a release of a hydrogen ion, a phosphate and a dUMP. The dUMP then interacts with a methenyltetrahydrofolate through a thymidylate synthase resulting in a dihydrofolic acid and a 5-thymidylic acid. Then 5-thymidylic acid is then phosphorylated through a nucleoside diphosphate kinase resulting in the release of an ADP and thymidine 5'-triphosphate.

Pyrimidines are heterocyclic aromatic organic compounds. These nitrogenous bases form an essential part of nucleic acids in DNA and RNA. Cytosine and thymine are inserted into the structure of DNA, while RNA utilizes cytosine and uracil. In metabolism, the pyrimidine is usually cleaved and the end products are typically beta-amino acids, ammonia and carbon dioxide. Pyrimidine metabolism in Arabidopsis thaliana occurs mostly in the nucleus, cytosol and chloroplast of the cell, with a few reactions taking place in the mitochondria, ER, vacuole, plasma membrane and peroxisome. The pyrimidines are incorporated into DNA in the compounds dTTP and dCTP. The apyrase enzyme or nucleoside diphosphate kinase-1 can convert dTTP to dTDP. Apyrase or thymidylate kinase can then convert dTDP to dTMP. Nucleotide diphosphatase can also metabolize dTTP directly to dTMP. The enzyme 5’-nucleotidase converts dTMP to thymidine. An unknown enzyme then metabolizes thymidine to thymine. Thymine is converted into dihydrothymine by dihydropyrimidine dehydrogenase. Dihydropyrimidinase converts dihydrothymine to 3-ureidoisobutyrate, which then forms 3-aminoisobutyrate via beta-ureidopropionase. Nucleotide diphosphate kinase-1 converts dCTP into dCDP, which produces dCMP via the enzyme UMP-CMP kinase-1. Two unknown enzymes metabolize dCMP to 2'-deoxy-5-hydroxymethylcytidine-5'-diphosphate which is then converted to 2'-deoxy-5-hydroxymethylcytidine-5’-triphosphate by nucleotide diphosphate kinase-1. Deoxycytidine is formed from dCMP by 5’-nucleotidase and is converted to deoxyuridine via cytidine deaminase. Thymidine kinase converts deoxyuridine to dUMP. The compound dUMP can also be formed from dCMP using dCMP deaminase. The dUMP formed is converted into dTMP by bifunctional dihydrofolate reductase-thymidylate synthase-1. The dTMP follows the metabolism pathway as previously mentioned to eventually form 3-aminoisobutyrate. The pyrimidines are incorporated into RNA in the compounds UTP and CTP. UTP is metabolised to UDP using the enzyme apyrase or nucleoside disphosphate kinase-1. UDP then forms UMP via apyrase or via the enzymes UMP-CMP kinase-1 and uridylate kinase. UMP can be directly formed from UTP using nucleotide diphosphatase. Uridine is produced from metabolism of UMP by the enzyme 5’-nucleotidase. Uridine nucleosidase-1 then forms uracil from uridine. Uracil phosphoribosyltransferase can also create uracil directly from UMP. Dihydrouracil is made from uracil via dihydropyrimidine dehydrogenase. Dihydropyrimidinase converts dihydrouracil to 3-ureidopropionate. Finally, β-alanine is generated from 3-ureidopropionate through the enzyme Beta-ureidopropionase. UTP can be converted into CTP via CTP synthase. CTP is then converted into CDP via apyrase or nucleoside disphosphate kinase-1. CDP forms dCDP via ribonucleoside-diphosphate reductase. The dCDP follows the metabolism pathway as previously mentioned, forming 3-aminoisobutyrate. CDP can also form CMP via apyrase or UMP-CMP kinase-1. CMP can be directly produced from CTP using nucleotide diphosphatase. Cytidine is then generated from the metabolism of CMP by 5’-nucleotidase. The cytidine formed can then be metabolized into uracil via cytidine deaminase. Uridine then follows the same metabolism pathway as previously mentioned to eventually form β-alanine.

A group of heterocyclic aromatic organic compound, pyrimidines are similar in structure to benzene and pyridine and count the nucleic acids cytosine, thymine, and uracil as structural derivatives. The following pathway illustrates a many pyrimidine-associated processes such as nucleotide biosynthesis, degradation, and salvage. This pathway depicts a number of pyrimidine-related processes such as nucleotide biosynthesis, degradation, and salvage. For pyrimidine nucleotide biosynthesis, carbamoyl phosphate derived from the action of carbamoyl phosphate synthetase II (CPS-II) on glutamine and bicarbonate is converted into carbamoyl aspartate by aspartate transcarbamoylase, ATCase. Dihydroorotic acid is subsequently generated by the action of carbamoyl aspartate dehydrogenase on carbamoyl aspartate. Dihydroorotate dehydrogenase then converts dihydroorotic acid to orotic acid. From this point, orotate phosphoribosyltransferase incorporates phosphoribosyl pyrophosphate into (PRPP) to produce orotidine monophosphate. Orotidine-5’-phosphate carboxylase subsequently converts orotidine monophosphate into uridine monophosphate (UMP). UMP is further phosphorylated twice to form UTP; the first instance by uridylate kinase and the second instance by ubiquitous nucleoside diphosphate kinase. UTP moves into the CTP synthesis pathway with the action of CTP synthase which aminates the molecule. The uridine nucleotides are also feedstock for the de novo thymine nucleotides synthesis pathway. DeoxyUMP which is derived from UDP or CDP metabolism is transformed by the action of thymidylate synthase into deoxyTMP of which the methyl group is sourced from N5,N10-methylene THF. THF is subsequently regenerated from DHF via dihydrofolate reductase (DHFR) which is essential for the continuation of thymidylate synthase activity. Serine hydroxymethyl transferase then acts on THF to regenerate N5,N10-THF. Pyrimidine synthesis is a comparatively simpler process than purine synthesis due to a couple of factors; pyrimidine ring structure is assembled as a free base rather being derived from PRPP and there is no branch in the pyrimidine synthesis pathway as opposed to the purine synthesis pathway. For thymidine, the action of thymidine kinase on it (or alternatively deoxyuridine) plays an important role in what is referred to as the salvage pathway to dTTP synthesis. However to form dTMP, the action of thymine phosphorylase and thymidine kinase is required. For deoxycytidine, deoxycytidine kinase is required (deoxycytidine also acts on deoxyadenosine and deoxyguanosine). For uracil, UMP can be formed by the action of uridine phosphorylase and uridine kinase on uracil. Pyrimidine catabolism ultimately results in the formation of the waste products of urea, H2O, and CO2. The product of cytosine breakdown, uracil, can be broken down to N-carbamoyl-β-alanine which can be catabolized into β-alanine. The product of thymine breakdown is β-aminoisobutyrate. The transamination of α-ketoglutarate to glutamate requires both of these breakdown products (β-alanine and β-aminoisobutyrate) to act as amine group donors. The products of this transamination can move through a further reaction that produces malonyl-CoA or methylmalonyl-CoA, a precursor for succinyl-CoA which is used in the Krebs cycle.