Browsing pathways

The metabolism of propionic acid (propanoate) begins with its conversion to propionyl coenzyme A (propionyl-CoA), which is the usual first step in the metabolism of carboxylic acids. Since propanoate has three carbons, propionyl-CoA cannot directly enter either the beta oxidation nor the citric acid cycles. In most vertebrates, propionyl-CoA is carboxylated to D-methylmalonyl-CoA, which is isomerised to L-methylmalonyl-CoA. A vitamin B12-dependent enzyme, called methylmalonyl CoA mutase catalyzes the rearrangement of L-methylmalonyl-CoA to succinyl-CoA, which is an intermediate of the citric acid cycle. Malonyl-CoA, another product of propanoate metabolism, is also used in transporting alpha-ketoglutarate across the mitochondrial membrane into the mitochondrial matrix. Malonyl-CoA is formed by carboxylating acetyl-CoA using the enzyme acetyl-CoA carboxylase. One molecule of acetyl-CoA joins with a molecule of carbon dioxide, requiring energy rendered from ATP.

Proparacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Proparacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore proparacaine preferentially inhibits neurons that are actively firing.

Propionic acidemia (Ketotic hyperglycinemia) is caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA or PCCB. Propionyl-CoA carboxylase (PCC), comprised of alpha and beta subunits, catalyzes the first step in the catabolism of propionyl-CoA, an important intermediate in the metabolism of several amino acids. A mutation in this enzyme causes accumulation of ammonia and propionylcarnitine (C3) in the blood; carnitine , glutamine, glycine, and propionic acid in the plasma; 3-hydroxypropionic acid, 3-hydroxyvaleric acid, 5-oxoproline, acylcarnitin, glycine, methylcitric acid, propionylglycine and tiglylcine in the urine. Symptoms include cardio myopathy, growth retardation, hypothermia, ketosis, neutropenia, strokelike episodes, pyloric stenosis and spastic diplegia/quadriplegia.

Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Higher doses of atenolol also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles.

Folates are essential cofactors that provide one-carbon moieties in various states of reduction for biosynthetic reactions. The processes shown in this pathway include transport reactions by which folates are taken up by cells and moved intracellularly, folate conjugation with glutamate (required for folate retention within a cell), as well as the synthesis of pterines, which are used in folate synthesis. Two branches are depicted: Pterin synthesis and Folate biosynthesis. In pterin synthesis, GTP is the precursor for pterin biosynthesis. The enzyme GTP-cyclohydrolase I produces dihydroneopterin triphosphate from GTP as the first step. The product is then dephosphorylated to dihydroneopterin and yields, after removal of a C2-residue from the C3-side chain 6- hydroxymethyldihydropterin, which is the precursor for folate biosynthesis. In terms of folate biosynthesis, the basic steps are: folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF. More specifically, the pathway leading to the formation of tetrahydrofolate (FH4) begins when folate (F) is reduced to dihydrofolate (DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. Another form of THF, formyl-THF (or folinic acid) results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF.

Purines are heterocyclic aromatic organic compounds, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable purines are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. Purines are found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The major site of purine nucleotide synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP). IMP synthesis begins with 5-phospho-α-ribosyl-1-pyrophosphate, PRPP. Through a series of reactions utilizing ATP, tetrahydrofolate (THF) derivatives, glutamine, glycine and aspartate this pathway yields IMP. The rate limiting reaction is catalyzed by glutamine PRPP amidotransferase which drives the reaction with PRPP and glutamine yielding 5-phosphoribosylamine (PRA). 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted to succinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP represents a branch point for purine biosynthesis, because it can be converted into either AMP or GMP through two distinct reaction pathways. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Catabolism of purine nucleotides ultimately leads to the production of uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. The free purine bases, adenine, guanine, and hypoxanthine, can be reconverted to their corresponding nucleotides by phosphoribosylation. Two key transferase enzymes are involved in the salvage of purines: adenosine phosphoribosyltransferase (APRT), which catalyzes the conversion of adenine to AMP and hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the conversion of hypoxanthine to IMP.

Purine nucleoside phosphorylase deficiency (Nucleoside phosphorylase; Immunodeficiency) is caused by a disruption of the purine nucleoside phosphorylase, a key enzyme in the purine salvage pathway. This enzyme is required for purine degradation. Specifically, it catalyzes the conversion of inosine and guanosine to hypoxanthine. A deficiency of it leads to build up of elevated deoxy-GTP (dGTP) levels resulting in T-cell toxicity and deficiency. A defect purine nucleoside phosphorylase results in accumulation of guanosine, inosine, and uric acid in serum; and orotic acid in some cases in the urine. Symptoms include anemia, ataxia, hypotonia, lymphopenia, mental retardation, and tremor or twitching.

Pyrimidines are heterocyclic aromatic organic compounds similar to benzene and pyridine. Cytosine, thymine, and uracil are pyrimidine derivatives. Synthesis of the pyrimidines is less complex than that of the purines, since the base is much simpler This pathway depicts a number of processes including pyrimidine nucleotide biosynthesis, pyrimidine degradation and pyrimidine salvage. Pyrimidine nucleotide biosynthesis begins with carbamoyl phosphate. The carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from glutamine and bicarbonate and is catalyzed by carbamoyl phosphate synthetase II (CPS-II). Subsequently carbamoyl phosphate is incorporated into the pyrimidine nucleotide biosynthesis pathway through the action of aspartate transcarbamoylase, ATCase which generates carbamoyl aspartate. This is then converted to dihydroorotic acid via carbamoyl aspartate dehydrogenase, which is then converted to orotic acid via dihydroorotate dehydrogenase. The enzyme orotate phosphoribosyltransferase incorporate PRPP to produce orotidine monophosphate (OMP) which is converted to UMP (uridine monopohophsate) via orotidine-5’-phosphate carboxylase. Following completion of UMP synthesis it can be phosphorylated to UTP and utilized as a substrate for CTP synthase for the synthesis of CTP. Specifically, UMP is phosphorylated twice to yield UTP. The first phosphorylation is catalyzed by uridylate kinase and the second by ubiquitous nucleoside diphosphate kinase. Finally UTP is aminated by the action of CTP synthase, generating CTP. Uridine nucleotides are also the precursors for de novo synthesis of the thymine nucleotides. The de novo pathway to thymidine nucleotdie synthesis first requires the use of deoxyUMP from the metabolism of either UDP or CDP. The deoxyUMP is converted to deoxyTMP by the action of thymidylate synthase. The methyl group is donated by N5,N10-methylene THF. In order for the thymidylate synthase reaction to continue, THF must be regenerated from DHF. This is accomplished through the action of dihydrofolate reductase (DHFR). THF is then converted to N5,N10-THF via the action of serine hydroxymethyl transferase. The synthesis of pyrimidines differs in two significant ways from that of purines. First, the ring structure is assembled as a free base, not built upon PRPP. Second, there is no branch in the pyrimidine synthesis pathway. The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can use either thymidine or deoxyuridine as a substrate. Uracil can be salvaged to form UMP through the concerted action of uridine phosphorylase and uridine kinase. Formation of dTMP, by salvage of dTMP requires the action of thymine phosphorylase and thymidine kinase while the salvage of deoxycytidine is catalyzed by deoxycytidine kinase. Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidine kinase. In terms of the catabolism of pyrimidines, they are ultimately degraded to CO2, H2O, and urea. Cytosine can be broken down to uracil which can be further broken down to N-carbamoyl-beta-alanine and then to beta-alanine. Thymine is broken down into β-aminoisobutyrate. The β-alanine and β-aminoisobutyrate serve as -NH2 donors in the transamination of α-ketoglutarate to glutamate. A subsequent reaction converts the products to malonyl-CoA or methylmalonyl-CoA (which is converted to succinyl-CoA and can be shunted to the TCA cycle).

This Pyruvaldehyde degradation pathway (Methylglyoxal degradation;2-oxopropanal degradation), also known as the glyoxalase system, is probably the most common pathway for the degradation of pyruvaldehyde (methylglyoxal), a potentially toxic metabolite due to its interaction with nucleic acids and other proteins. Pyruvaldehyde is formed in low concentrations by glycolysis, fatty acid metabolism and protein metabolism. Pyruvaldehyde is catalyzed by the glyoxylase system, composed of the enzymes lactoylglutathione lyase (glyoxalase I) and glyoxylase II. Glyoxalase I catalyes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and pyruvaldehyde into S-lactoylglutathione. S-lactoylglutathione is then catalyzed by glyoxalase II into D-lactic acid and glutathione. D-lactic acid is then catalyzed by an unknown quinol in the membrane to pyruvic acid, which then enters pyruvate metabolism.

Pyruvate carboxylase deficiency is caused by mutation in the pyruvate carboxylase gene. Serine--pyruvate aminotransferase catalyzes the reaction of serine and pyruvate to produce 3-hydroxypyruvate and L-alanine, as well as the reaction from L-alanine and glyodxylate to pyruvate and glycine. A defect in this results in accumulation of ammonia, glucose and pyruvate in blood; proline, lysine, citrulline, and alanine in plasma; and 2-oxoglutaric acid, fumaric acid, ketone bodies and succinate in urine. Symptoms include ataxia, lactic acidosis, mental retardation, metabolic acidosis, siezures, and dyspnea.