Chondroitin

Chondroitin is a mucopolysaccharide constituent of chondrin. Chondrin is a gelatin-like protein-carbohydrate substance that can be obtained by boiling cartilage in water. Cartilage is a connective tissue that contains cells embedded in a matrix of chondrin. Chondroitin is a glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetyl-galactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. The structure depicted in this MetaboCard is simply a disaccharide component of the chontroitin subunit. Chondroitin's functions largely depend on the properties of the overall proteoglycan of which it is a part. These functions can be broadly divided into structural and regulatory roles. However, this division is not absolute and some proteoglycans have both structural and regulatory roles. Chondroitin is an ingredient found commonly in dietary supplements used as an alternative medicine to treat osteoarthritis. It is commonly sold together with glucosamine. The dosage of oral chondroitin used in human clinical trials is 800-1200 mg per day. Most chondroitin appears to be made from extracts of cartilaginous cow and pig tissues (cow trachea and pig ear and nose), but other sources such as shark, fish and bird cartilage are also used. Since chondroitin is not a uniform substance, and is naturally present in a wide variety of forms, the precise composition of each supplement will vary. While it is a prescription or over-the-counter drug in 22 countries, chondroitin is regulated in the U.S. as a food product by the Food and Drug Administration. As a result, there are no mandatory standards for formulation, and no guarantee that the product is correctly labelled.


Chondroitin sulfate

Chondroitin 4-sulfate is a derivative of chondroitin which has a sulfate moiety esterified to the galactosamine moiety of chondroitin. Chondroitin sulfate A, or chondroitin 4-sulfate, and chondroitin sulfate C, or chondroitin 6-sulfate, have the sulfate esterified in the 4- and 6-positions, respectively. Chondroitin sulfate B (beta heparin; DERMATAN SULFATE) is a misnomer and this compound is not a true chondroitin sulfate. An example structure is given, and this Chondroiton sulfate is a polymer that can contain up to 100 individual sugars.

Chondroitin 4'-sulfate
Chondroitin sulfate a
Chondroitin 4'-sulphate
Chondroitin sulphate a


phytanic acid

Phytanic acid (or 3,7,11,15-tetramethylhexadecanoic acid) is a 20-carbon branched-chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. It is primarily formed by bacterial degradation of chlorophyll in the intestinal tract of ruminants. Unlike most fatty acids, phytanic acid cannot be metabolized by beta-oxidation (because of a methyl group in the beta position). Instead, it undergoes alpha-oxidation in the peroxisome, where it is converted into pristanic acid by the removal of one carbon. Pristanic acid can undergo several rounds of beta-oxidation in the peroxisome to form medium-chain fatty acids that can be converted into carbon dioxide and water in mitochondria. Refsum disease, an autosomal recessive neurological disorder caused by mutations in the PHYH gene, is characterized by having impaired alpha-oxidation activity. Individuals with Refsum disease accumulate large stores of phytanic acid in their blood and tissues. This frequently leads to peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, anosmia, and hearing loss. Therefore, chronically high levels of phytanic acid can be neurotoxic. Phytanic acid's neurotoxicity appears to lie in its ability to initiate astrocyte/neural cell death by activating the mitochondrial route of apoptosis. In particular, phytanic acid can induce the substantial generation of reactive oxygen species in isolated mitochondria as well as in intact cells. It also induces the release of cytochrome c from mitochondria.

3,7,11,15-tetramethyl-hexadecanoate
3,7,11,15-tetramethyl-hexadecanoic acid
3,7,11,15-tetramethyl-hexadecansaeure
3,7,11,15-tetramethylhexadecanoate
3,7,11,15-tetramethylhexadecanoic acid
3,7,11,15-tetramethylhexadecoanoate
3,7,11,15-tetramethylhexadecoanoic acid
Phytanate
Phytanoate
Phytanoic acid
3,7,11,15-tetramethyl hexadecanoic acid
3,7,11,15-tetramethyl hexadecanoate


phytanoyl-CoA

Phytanoyl CoA is a coenzyme A derivative of phytanic acid. Phytanic acid is present in human diet or in animal tissues where it may be derived from chlorophyll in plant extracts. Specifically it is an epimeric metabolite of the isoprenoid side chain of chlorophyll. Owing to the presence of its epimeric beta-methyl group, phytanic acid cannot be metabolized by beta-oxidation. Instead, it is metabolized in peroxisomes via alpha-oxidation to give pristanic acid, which is then oxidized by beta-oxidation. PhyH (phytanoyl-CoA 2-hydroxylase) catalyses hydroxylation of phytanoyl-CoA. Mutations of PhyH can lead to phytanic acid accumulation. High levels of phytanic acid are found in patients suffering from Refsum's syndrome. This inherited neurological disorder is characterized by an accumulation of phytanic acid in blood and tissues. Clinically it is characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia. This disorder has been found to be related to deficiency in the α-oxidation pathway in the liver. (PMID: 17956235). Phytanoyl CoA and other branched-chain fatty acid CoA products are potent inducers of the peroxisome proliferator-activated receptor PPARalpha, a nuclear receptor that enhances transcription of peroxisomal enzymes mediating beta-oxidation of these potentially toxic fatty acids (PMID: 16768463). Pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase are strongly inhibited by phytanoyl-CoA. Decreased activity of these important mitochondrial metabolism complexes might therefore contribute to neurological symptoms upon accumulation of phytanic acid in Refsum disease (PMID: 16737698).

3,7,11,15-tetramethyl hexadecanoyl coenzyme a


2-Hydroxyphytanoyl-CoA belongs to the class of organic compounds known as long-chain fatty acyl coas. These are acyl CoAs where the group acylated to the coenzyme A moiety is a long aliphatic chain of 13 to 21 carbon atoms. Thus, 2-hydroxyphytanoyl-CoA is considered to be a fatty ester lipid molecule. 2-Hydroxyphytanoyl-CoA is slightly soluble (in water) and an extremely strong acidic compound (based on its pKa). 2-Hydroxyphytanoyl-CoA has been primarily detected in urine. Within the cell, 2-hydroxyphytanoyl-CoA is primarily located in the peroxisome, cytoplasm and mitochondria. In humans, 2-hydroxyphytanoyl-CoA is involved in the oxidation OF branched chain fatty acids pathway and the phytanic Acid peroxisomal oxidation pathway. 2-Hydroxyphytanoyl-CoA is also involved in the metabolic disorder called the refsum disease pathway. 2-Hydroxyphytanoyl-CoA is a substrate for Phytanoyl-CoA dioxygenase (peroxisomal).


pristanal

Pristanal belongs to the class of organic compounds known as acyclic diterpenoids. These are diterpenoids (compounds made of four consecutive isoprene units) that do not contain a cycle. Thus, pristanal is considered to be an isoprenoid lipid molecule. Pristanal is considered to be a practically insoluble (in water) and relatively neutral molecule. Within the cell, pristanal is primarily located in the cytoplasm, membrane (predicted from logP) and peroxisome. In humans, pristanal is involved in the oxidation OF branched chain fatty acids pathway and the phytanic Acid peroxisomal oxidation pathway. Pristanal is also involved in the metabolic disorder called the refsum disease pathway. Intermediate in the metabolism of phytanic acid and pristanic acid.


formyl-CoA

Formyl-CoA is formed during the alpha-oxidation process in liver peroxisomes, as a result of the alpha-oxidation of 3-methyl-substituted fatty acids. The amount of formyl-CoA formed constitutes 2 - 5% of the total formate. The formyl-CoA formed is not due to activation of formate - until now presumed to be the primary end-product of alpha-oxidation - but is rather than formate the end-product of alpha-oxidation. The cleavage of 2-hydroxy-3-methylhexadecanoyl-CoA to 2-methylpentadecanal and formate (formyl-CoA) is probably due to the presence of a specific lyase. (PMID: 9276483, 9166898).


pristanic acid

Pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) is a terpenoid acid present at micromolar concentrations in the plasma of healthy individuals. It is also found in the lipids from many sources such as freshwater sponges, krill, earthworms, whales, human milk fat, bovine depot fat, butterfat or Californian petroleum. It is usually present in combination with phytanic acid. In humans, pristanic acid is obtained from two sources: either directly from the diet or as the alpha oxidation product of phytanic acid. At physiological concentrations pristanic acid is a natural ligand for PPARalpha. In liver, pristanic acid is degraded by peroxisomal beta oxidation to propionyl-CoA. Together with phytanic acid, pristanic acid accumulates in several inherited disorders such as Zellweger syndrome. Pristanic acid is a branched chain fatty acid that arises from the breakdown of phytanic acid. It is present at micromolar concentrations in the plasma of healthy individuals. Pristanic acid is normally degraded by peroxisomal beta-oxidation. In patients affected with generalized peroxisomal disorders, degradation of both phytanic acid and pristanic acid is impaired owing to absence of functional peroxisomes. Pristanic acid has been found to activate the peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) in a concentration dependent manner.


Propanoyl-CoA

Propionyl-CoA is an intermediate in the metabolism of propanoate. Propionic aciduria is caused by an autosomal recessive disorder of propionyl coenzyme A (CoA) carboxylase deficiency (EC 6.4.1.3). In propionic aciduria, propionyl CoA accumulates within the mitochondria in massive quantities; free carnitine is then esterified, creating propionyl carnitine, which is then excreted in the urine. Because the supply of carnitine in the diet and from synthesis is limited, such patients readily develop carnitine deficiency as a result of the increased loss of acylcarnitine derivatives. This condition demands supplementation of free carnitine above the normal dietary intake to continue to remove (detoxify) the accumulating organic acids. Propionyl-CoA is a substrate for Acyl-CoA dehydrogenase (medium-chain specific, mitochondrial), Acetyl-coenzyme A synthetase 2-like (mitochondrial), Propionyl-CoA carboxylase alpha chain (mitochondrial), Methylmalonate-semialdehyde dehydrogenase (mitochondrial), Trifunctional enzyme beta subunit (mitochondrial), 3-ketoacyl-CoA thiolase (peroxisomal), Acyl-CoA dehydrogenase (long-chain specific, mitochondrial), Malonyl-CoA decarboxylase (mitochondrial), Acetyl-coenzyme A synthetase (cytoplasmic), 3-ketoacyl-CoA thiolase (mitochondrial) and Propionyl-CoA carboxylase beta chain (mitochondrial). (PMID: 10650319).

2-methylacetyl-coa
2-methylacetyl-coenzyme a
Propanoyl-coa
Propanoyl-coenzyme a
Propionyl-coa
Propionyl-coenzyme a
Alpha-methylacetyl-coa
Alpha-methylacetyl-coenzyme a


isobutyryl-CoA

Isobutyryl-CoA, also known as isobutanoyl-coa, belongs to the class of organic compounds known as acyl coas. These are organic compounds containing a coenzyme A substructure linked to an acyl chain. Thus, isobutyryl-CoA is considered to be a fatty ester lipid molecule. Isobutyryl-CoA is slightly soluble (in water) and an extremely strong acidic compound (based on its pKa). Isobutyryl-CoA has been primarily detected in urine. Within the cell, isobutyryl-CoA is primarily located in the mitochondria and cytoplasm. Isobutyryl-CoA exists in all living organisms, ranging from bacteria to humans. In humans, isobutyryl-CoA is involved in the phytanic Acid peroxisomal oxidation pathway and the valine, leucine and isoleucine degradation pathway. Isobutyryl-CoA is also involved in several metabolic disorders, some of which include methylmalonate semialdehyde dehydrogenase deficiency, the maple syrup urine disease pathway, the 3-methylglutaconic aciduria type I pathway, and the isovaleric acidemia pathway. Isobutyryl-CoA is a substrate for Acyl-CoA dehydrogenase (short-chain specific, mitochondrial), Acyl-CoA dehydrogenase (medium-chain specific, mitochondrial) and Acyl-CoA dehydrogenase (long-chain specific, mitochondrial).

2-methylpropanoyl-coa
2-methylpropanoyl-coenzyme a
2-methylpropionyl-coa
2-methylpropionyl-coenzyme a
Isobutyryl- coa
Isobutyryl- coenzyme a
Isobutyryl-coa
S-(2-methylpropanoate
S-(2-methylpropanoate)coa
S-(2-methylpropanoate)coenzyme a
S-(2-methylpropanoic acid
S-(2-methylpropanoyl)-coa
S-(2-methylpropanoyl)-coenzyme a
Alpha-methylpropionyl-coa
Alpha-methylpropionyl-coenzyme a
Isobutanoyl-coa


Phenylalanine

Phenylalanine is an essential amino acid and the precursor of the amino acid tyrosine. Like tyrosine, phenylalanine is also a precursor for catecholamines including tyramine, dopamine, epinephrine, and norepinephrine. Catecholamines are neurotransmitters that act as adrenalin-like substances. Interestingly, several psychotropic drugs (mescaline, morphine, codeine, and papaverine) also have phenylalanine as a constituent. Phenylalanine is highly concentrated in the human brain and plasma. Normal metabolism of phenylalanine requires biopterin, iron, niacin, vitamin B6, copper, and vitamin C. An average adult ingests 5 g of phenylalanine per day and may optimally need up to 8 g daily. Phenylalanine is highly concentrated in a number of high protein foods, such as meat, cottage cheese, and wheat germ. An additional dietary source of phenylalanine is artificial sweeteners containing aspartame. As a general rule, aspartame should be avoided by phenylketonurics and pregnant women. When present in sufficiently high levels, phenylalanine can act as a neurotoxin and a metabotoxin. A neurotoxin is a compound that disrupts or attacks neural cells and neural tissue. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of phenylalanine are associated with at least five inborn errors of metabolism, including Hartnup disorder, hyperphenylalaninemia due to guanosine triphosphate cyclohydrolase deficiency, phenylketonuria (PKU), tyrosinemia type 2 (or Richner-Hanhart syndrome), and tyrosinemia type III (TYRO3). Phenylketonurics have elevated serum plasma levels of phenylalanine up to 400 times normal. High plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into the brain and restrict the entry of other large neutral amino acids (PMID: 19191004). Phenylalanine has been found to interfere with different cerebral enzyme systems. Untreated phenylketonuria (PKU) can lead to intellectual disability, seizures, behavioural problems, and mental disorders. It may also result in a musty smell and lighter skin. Classic PKU dramatically affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological disorders associated with phenylketonuria. Mild phenylketonuria can act as an unsuspected cause of hyperactivity, learning problems, and other developmental problems in children. It has been recently suggested that PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine (PMID: 22706200). Phenylalanine also has some potential benefits. Phenylalanine can act as an effective pain reliever. Its use in premenstrual syndrome and Parkinson's may enhance the effects of acupuncture and electric transcutaneous nerve stimulation (TENS). Phenylalanine and tyrosine, like L-DOPA, produce a catecholamine-like effect. Phenylalanine is better absorbed than tyrosine and may cause fewer headaches. Low phenylalanine diets have been prescribed for certain cancers with mixed results. For instance, some tumours use more phenylalanine than others (particularly melatonin-producing tumours called melanomas).


PHENYLPYRUVATE

Phenylpyruvic acid is a keto-acid that is an intermediate or catabolic byproduct of phenylalanine metabolism. It has a slight honey-like odor. Levels of phenylpyruvate are normally very low in blood or urine. High levels of phenylpyruvic acid can be found in the urine of individuals with phenylketonuria (PKU). PKU is due to lack of the enzyme phenylalanine hydroxylase (PAH), so that phenylalanine is converted not to tyrosine but to phenylpyruvic acid. In particular, excessive phenylalanine can be metabolized into phenylketones through, a transaminase pathway route involving glutamate. Metabolites of this transamination reaction include phenylacetate, phenylpyruvate and phenethylamine. In persons with PKU, dietary phenylalanine either accumulates in the body or some of it is converted to phenylpyruvic acid. Individuals with PKU tend to excrete large quantities of phenylpyruvate, phenylacetate and phenyllactate, along with phenylalanine, in their urine. If untreated, mental retardation effects and microcephaly are evident by the first year along with other symptoms which include: unusual irritability, epileptic seizures and skin lesions. Hyperactivity, EEG abnormalities and seizures, and severe learning disabilities are major clinical problems later in life. A "musty or mousy" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed. The neural-development effects of PKU are primarily due to the disruption of neurotransmitter synthesis. In particular, phenylalanine is a large, neutral amino acid which moves across the blood-brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development, leading to mental retardation.

2-oxo-3-phenylpropanoic acid (mixture oxo and keto)


Sapropterin

L-Erythro-tetrahydrobiopterin, also known as R-THBP or 6R-BH4, belongs to the class of organic compounds known as biopterins and derivatives. These are coenzymes containing a 2-amino-pteridine-4-one derivative. They are mainly synthesized in several parts of the body, including the pineal gland. L-Erythro-tetrahydrobiopterin is a drug which is used for the treatment of tetrahydrobiopterin (bh4) deficiency. L-Erythro-tetrahydrobiopterin exists as a solid, slightly soluble (in water), and a very weakly acidic compound (based on its pKa). In humans, L-erythro-tetrahydrobiopterin is involved in the phenylalanine and tyrosine metabolism pathway. L-Erythro-tetrahydrobiopterin is also involved in a few metabolic disorders, which include the tyrosinemia type 2 (or richner-hanhart syndrome) pathway, the phenylketonuria pathway, and the tyrosinemia type 3 (tyro3) pathway. L-erythro-tetrahydrobiopterin is part of the Folate biosynthesis pathway. It is a substrate for: Sepiapterin reductase.


Tetrahydrobiopterin (BH4) is essential to catalyze the conversion of phenylalanine to tyrosine by phenylalanine hydroxylase. During this physiological reaction, the oxidation of BH4 creates 4a-hydroxytetrahydropterin intermediates and hydrogen peroxide is formed. The hydrogen peroxide and the hydroxytetrahydropterin can both derive from alternate routes of breakdown of a common precursor, the corresponding 4a-hydroperoxytetrahydropterin. (PMID 8323303).


4-Hydroxyphenylpyruvic acid

4-Hydroxyphenylpyruvic acid (4-HPPA) is a keto acid that is involved in the tyrosine catabolism pathway. It is a product of the enzyme (R)-4-hydroxyphenyllactate dehydrogenase [EC 1.1.1.222] and is formed during tyrosine metabolism. The conversion from tyrosine to 4-HPPA is catalyzed by tyrosine aminotransferase. Additionally, 4-HPPA can be converted to homogentisic acid which is one of the precursors to ochronotic pigment. The enzyme 4-hydroxyphenylpyruvic acid dioxygenase (HPD) catalyzes the reaction that converts 4-hydroxyphenylpyruvic acid to homogentisic acid. A deficiency in the catalytic activity of HPD is known to lead to tyrosinemia type III, an autosomal recessive disorder characterized by elevated levels of blood tyrosine and massive excretion of tyrosine derivatives into urine. It has been shown that hawkinsinuria, an autosomal dominant disorder characterized by the excretion of 'hawkinsin,' may also be a result of HPD deficiency (PMID: 11073718). There are two isomers of HPPA, specifically 4HPPA and 3HPPA, of which 4HPPA is the most common.


Homogentisate

Homogentisic acid, also known as melanic acid, is an intermediate in the breakdown or catabolism of tyrosine and phenylalanine. It is generated from the compound p-hydroxyphenylpyruvate through the enzyme p-hydroxyphenylpyruvate dehydrogenase. The resulting homogentisic acid is then broken down into 4-maleylacetoacetate via the enzyme homogentisate 1,2-dioxygenase. Homogentisic acid is also found in other organisms. For instance, it can found in Arbutus unedo (strawberry-tree) honey, in the bacterial plant pathogen Xanthomonas campestris as well as in the yeast Yarrowia lipolytica where it is associated with the production of brown pigments. Homogentisic acid can be oxidatively dimerized to form hipposudoric acid, one of the main constituents of the 'blood sweat' of hippopotamuses. When present in sufficiently high levels, homogentisic acid can function as an osteotoxin and a renal toxin. An osteotoxin is a substance that causes damage to bones and/or joints. A renal toxin causes damage to the kidneys. Chronically high levels of homogentisic acid are associated with alkaptonuria (OMIM: 203500), an inborn error of metabolism. Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine. It is caused by a mutation in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which leads to an accumulation of homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form benzoquinone acetic acid are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid (and benzoquinone acetic acid) causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. More specifically, homogentisic acid can be converted to benzoquinone acetic acid (BQA), and the resulting BQA can be readily converted to polymers that resemble the dark skin pigment melanin. These polymers are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage. Homogentisic acid is the primary precursor of melanin synthesis in Vibrio cholerae.

(2,5-dihydroxyphenyl)-acetate
(2,5-dihydroxyphenyl)-acetic acid
2,5-dihydroxy-a-toluate
2,5-dihydroxy-a-toluic acid
2,5-dihydroxy-alpha-toluate
2,5-dihydroxy-alpha-toluic acid
2,5-dihydroxy-benzeneacetate
2,5-dihydroxy-benzeneacetic acid
2,5-dihydroxyphenylacetate
2,5-dihydroxyphenylacetic acid
Alcapton
Homogentisate
Homogentisate acid
Homogentisinate
Homogentisinic acid
Melanic acid
2-(3,6-dihydroxyphenyl)acetic acid
2-(3,6-dihydroxyphenyl)acetate


4-maleylacetoacetic acid

4-Maleylacetoacetate is an intermediate in the metabolism of tyrosine. Homogentisate 1,2-dioxygenase is the enzyme, which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the break down of the amino acids tyrosine and phenylalanine.

4-maleylacetoacetate
4-maleylacetoacetic acid
Maleylacetoacetate


4-fumarylacetoacetic acid

Fumarylacetoacetate is an intermediate in the metabolism of tyrosine. Fumarylacetoacetate hydrolase (FAH) is an enzyme which catalyzes the hydrolysis of 4-fumarylacetoacetate into fumarate and acetoacetate. FAH is the last enzyme in the tyrosine catabolism pathway. FAH deficiency is associated with Type 1 hereditary tyrosinemia.


Histamine

Histamine, also known as eramin or ceplene, belongs to the class of organic compounds known as 2-arylethylamines. These are primary amines that have the general formula RCCNH2, where R is an organic group. Histamine exists as a solid, soluble (in water), and a very weakly acidic compound (based on its pKa). Histamine has been found throughout most human tissues, and has also been detected in most biofluids, including feces, saliva, urine, and blood. Within the cell, histamine is primarily located in the myelin sheath. In humans, histamine is involved in the phenbenzamine H1-antihistamine action pathway, the omeprazole action pathway, the levocetirizine H1-antihistamine action pathway, and the propiomazine H1-antihistamine action pathway. Histamine is also involved in several metabolic disorders, some of which include the thiazinamium H1-antihistamine action pathway, the metiamide action pathway, the quetiapine H1-antihistamine action pathway, and the histidinemia pathway. Outside of the human body, histamine can be found in a number of food items such as daikon radish, jicama, caraway, and japanese walnut. This makes histamine a potential biomarker for the consumption of these food products. Histamine is an amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter.


N(tele)-methylhistamine

1-Methylhistamine belongs to the class of organic compounds known as 2-arylethylamines. These are primary amines that have the general formula RCCNH2, where R is an organic group. 1-Methylhistamine is slightly soluble (in water) and a very strong basic compound (based on its pKa). 1-Methylhistamine has been found in human bone marrow and brain tissues, and has also been detected in most biofluids, including saliva, cerebrospinal fluid, feces, and blood. Within the cell, 1-methylhistamine is primarily located in the cytoplasm. In humans, 1-methylhistamine is involved in the histidine metabolism pathway. 1-Methylhistamine is also involved in the metabolic disorder called the histidinemia pathway. 1-Methylhistamine is a histamine metabolite. It is a product of histamine 1-methyltransferase [EC 2.1.1.8] in the pathway histidine metabolism (KEGG).


Methyimidazole acetaldehyde is a metabolite of histamine. The metabolites of ethanol and acetaldehyde can successfully compete with methylimidazole acetaldehyde, since the alcohol and histamine metabolic pathways in the body have two enzymes in common, aldehyde dehydrogenase and aldehyde oxidase. (PMID: 10344773).

1-methylimidazole-4-acetaldehyde
Methylimidazoleacetaldehyde
Methylimidazole acetaldehyde


1-methyl-4-imidazoleacetic acid

Methylimidazoleacetic acid is the main metabolite of histamine. This end product of histamine catabolism is formed by N-methylation in the imidazole ring to methylhistamine by histamine methyltransferase (EC 2.1.1.8) and a subsequent oxidative deamination in the side chain by type B monoamine oxidase (EC 1.4.3.4). Based on studies, it is known that as much as 70 to 80 percent of the histamine metabolized in the body is excreted in the urine as methylimidazoleacetic acid. Thus, urinary methylimidazoleacetic acid being the major and specific histamine metabolite is a clear marker of any changes in histamine metabolism in the body. The urinary excretion of methylimidazoleacetic acid is considered a reliable indicator of histamine turnover rate in the body. The excretion of methylimidazoleacetic acid is higher in men than in women. However, this gender difference is abolished when corrected for creatinine excretion. A possible explanation is that basal histamine turnover is related to body size. There is no significant difference in methylimidazoleacetic acid excretion between smokers and non-smokers when analyzing absolute values (mg/24 h). When using methylimidazoleacetic acid values corrected for creatinine excretion female smokers have significantly higher methylimidazoleacetic acid excretion compared to nonsmokers (PMID: 11411609, 7130180, 10350179, 10202992).


Imidazole-4-acetaldehyde is a naturally occurring aldehyde metabolite of histamine formed by the action of histaminase (E.C. 1.4.3.6), and can be synthesized by oxidation of histidine. Aldehyde dehydrogenase (EC 1.2.1.3) is the only enzyme in the human liver capable of catalyzing dehydrogenation of aldehydes arising via monoamine, diamine, and plasma amine oxidases. NAD-linked dehydrogenation of short chain aliphatic aldehydes has been found in virtually every organ of the mammalian body. Imidazole-4-acetaldehyde is a good substrate for all aldehyde dehydrogenase isozymes. Experimentally, the prebiotic formation of histidine has been accomplished by the reaction of erythrose with formamidine followed by a Strecker synthesis. Imidazole-4-acetaldehyde could have been converted to histidine on the primitive earth by a Strecker synthesis, and several prebiotic reactions could convert imidazole-4-glycol and imidazole-4-ethanol to imidazole-4-acetaldehyde. (PMID: 2071588, 2957640, 11536478).


CID 28305488

Imidazoleacetic acid, also known as 4(5)-imidazoleacetate or imac, belongs to the class of organic compounds known as imidazolyl carboxylic acids and derivatives. These are organic compounds containing a carboxylic acid chain (of at least 2 carbon atoms) linked to an imidazole ring. Imidazoleacetic acid is soluble (in water) and a weakly acidic compound (based on its pKa). Imidazoleacetic acid has been primarily detected in feces, urine, blood, and cerebrospinal fluid. Within the cell, imidazoleacetic acid is primarily located in the cytoplasm and mitochondria. In humans, imidazoleacetic acid is involved in the histidine metabolism pathway. Imidazoleacetic acid is also involved in the metabolic disorder called the histidinemia pathway. Outside of the human body, imidazoleacetic acid can be found in a number of food items such as pepper (c. frutescens), black-eyed pea, rambutan, and common hazelnut. This makes imidazoleacetic acid a potential biomarker for the consumption of these food products. Imidazoleacetic acid is a metabolite product of Histamine metabolism. It is present in normal urine and increased in histidinemic patients. (PMID 6530403).

1h-imidazol-4-ylacetic acid
1h-imidazole-4-acetic acid
4(5)-imidazoleacetate
4-imidazoleacetate
4-imidazoleacetic acid
Iaa
Imac
Izc
Imidazol-4-ylacetic acid
Imidazole acetate
Imidazole-4-acetate
Imidazole-4-acetic acid
Imidazolyl-4-acetic acid
Lopac-i-0375
Imidazoleacetic acid
1h-imidazole-4-acetate
Imidazol-4-ylacetate
4(5)-imidazoleacetic acid
Imidazoleacetate


4-Imidazolone-5-propanoate is a metabolite of histidine metabolism. It is produced from urocanic acid by the enzyme urocanate hydratase [EC:4.2.1.49]. 4-Imidazolone-5-propionic acid can spontaneously decay to 4-oxoglutaramate or formylisoglutamine. It is also converted to N-forminimo-L-glutamate by the enzyme imidazolonepropionase [EC:3.5.2.7].


N-formimidoyl-L-glutamic acid

Formiminoglutamic acid, also known as N-formimino-L-glutamate or acid, formiminoglutamic, belongs to the class of organic compounds known as glutamic acid and derivatives. Glutamic acid and derivatives are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom. Formiminoglutamic acid is slightly soluble (in water) and a moderately acidic compound (based on its pKa). Formiminoglutamic acid has been detected in multiple biofluids, such as feces and urine. Within the cell, formiminoglutamic acid is primarily located in the cytoplasm. In humans, formiminoglutamic acid is involved in the histidine metabolism pathway. Formiminoglutamic acid is also involved in the metabolic disorder called the histidinemia pathway. Measurement of this acid in the urine after oral administration of histidine provides the basis for the diagnostic test of folic acid deficiency and of megaloblastic anemia of pregnancy.

Formimino-l-glutamate
Formimino-l-glutamic acid
Formimino-glu
Formiminoglutamate
N-(iminomethyl)-l-glutamic acid
N-formimidoyl-glutamic acid
N-formimidoyl-l-glutamate
N-formimidoyl-l-glutamic acid
N-formimino-l-glutamate
N-formimino-l-glutamic acid
N-formimino-glutamate


One-methylhistidine (1-MHis) is derived mainly from the anserine of dietary flesh sources, especially poultry. The enzyme, carnosinase, splits anserine into b-alanine and 1-MHis. High levels of 1-MHis tend to inhibit the enzyme carnosinase and increase anserine levels. Conversely, genetic variants with deficient carnosinase activity in plasma show increased 1-MHis excretions when they consume a high meat diet. Reduced serum carnosinase activity is also found in patients with Parkinson's disease and multiple sclerosis and patients following a cerebrovascular accident. Vitamin E deficiency can lead to 1-methylhistidinuria from increased oxidative effects in skeletal muscle.


20-hydroxy- Leukotriene B4 (20-OH-LTB4) is an omega-hydroxylated metabolite of leukotriene B4 in human neutrophils. Elevated urinary concentrations of 20-OH-LTB4 and LTB4 are found in patients with Sjogren-Larsson syndrome (SLS, OMIM 270220), an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH), which as an essential role in LTB4 metabolism. Preterm birth seems to be one of the features of the syndrome. The reason for the preterm birth is unclear. It is hypothesized that it relates to the defective LTB4 degradation in SLS. The pathological urinary excretion of LTB4 and 20-OH-LTB4 is a biochemical marker for SLS. Surprisingly, 20-OH-LTB4 concentrations are normal in CSF. Leukotriene B4 is the major metabolite in neutrophil polymorphonuclear leukocytes. Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by beta-oxidation from the w-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/ 15-oxo-prostaglandin-13-reductase that form a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a gamma-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before w-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease. (PMID: 12709426, 9799565, 11408337, 17623009). Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


20-hydroxy-20-oxoleukotriene B4

20-Carboxyleukotriene B4 is an omega-oxidized metabolite of leukotriene B4 (LTB4). Neutrophil microsomes are known to oxidize 20-hydroxy-LTB4 (20-OH-LTB4) to its 20-oxo and 20-carboxy derivatives in the presence of NADPH. This activity has been ascribed to LTB4 omega-hydroxylase (cytochrome P-450LTB omega). Leukotriene B4 release from polymorphonuclear granulocytes of severely burned patients was reduced as compared to healthy donor cells. This decrease is due to an enhanced conversion of LTB4 into the 20-hydroxy- and 20-carboxy-metabolites and further to a decreased LTB4-synthesis. LTB4 is the major metabolite in neutrophil polymorphonuclear leukocytes. Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by beta-oxidation from the w-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/ 15-oxo-prostaglandin-13-reductase that form a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a gamma-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before w-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease. (PMID 17623009, 7633595, 2155225, 3039534)Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Leukotriene B4

Leukotriene B4 is the major metabolite in neutrophil polymorphonuclear leukocytes. Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by b-oxidation from the w-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/ 15-oxo-prostaglandin-13-reductase that form a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a gamma-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before w-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease. The term leukotriene was coined to indicate the presence of three conjugated double bonds within the 20-carbon structure of arachidonic acid as well as the fact that these compounds were derived from leucocytes such as PMNNs or transformed mast cells. Interestingly, most of the cells known to express 5-LO are of myeloid origin, which includes neutrophils, eosinophils, mast cells, macrophages, basophils and monocytes. Leukotriene biosynthesis begins with the specific oxidation of arachidonic acid by a free radical mechanism as a consequence of interaction with 5-LO. The first enzymatic step involves the abstraction of a hydrogen atom from C-7 of arachidonate followed by the addition of molecular oxygen to form 5-HpETE (5-hydroperoxyeicosatetraenoic acid). A second enzymatic step is also catalysed by 5-LO and involves removal of a hydrogen atom from C-10, resulting in formation of the conjugated triene epoxide LTA4. LTA4 must then be released by 5-LO and encounter either LTA4-H (LTA4 hydrolase) or LTC4-S [LTC4 (leukotriene C4) synthase]. LTA4-H can stereospecifically add water to C-12 while retaining a specific double-bond geometry, leading to LTB4 [leukotriene B4, 5(S),12(R)-dihydroxy-6,8,10,14-(Z,E,E,Z)-eicosatetraenoic acid]. If LTA4 encounters LTC4-S, then the reactive epoxide is opened at C-6 by the thiol anion of glutathione to form the product LTC4 [5(S)-hydroxy-6(R)-S-glutathyionyl-7,9,11,14- (E,E,Z,Z)-eicosatetraenoic acid], essentially a glutathionyl adduct of oxidized arachidonic acid. Both of these terminal leukotrienes are biologically active in that specific GPCRs recognize these chemical structures and receptor recognition initiates complex intracellular signalling cascades. In order for these molecules to serve as lipid mediators, however, they must be released from the biosynthetic cell into the extracellular milieu so that they can encounter the corresponding GPCRs. Surprising features of this cascade include the recognition of the assembly of critical enzymes at the perinuclear region of the cell and even localization of 5-LO within the nucleus of some cells. Under some situations, the budding phagosome has been found to assemble these proteins. Non-enzymatic proteins such as FLAP are now known as critical partners of this protein-machine assembly. An unexpected pathway of leukotriene biosynthesis involves the transfer of the chemically reactive intermediate, LTA4, from the biosynthetic cell followed by conversion into LTB4 or LTC4 by other cells that do not express 5-LO. (PMID 17623009). Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.

5,12-dihydroxy-6,10-trans -8,14-cis -eicosatetraenoic acid


leukotriene A4

Leukotriene A4 (LTA4) is the first metabolite in the series of reactions leading to the synthesis of all leukotrienes. 5-Lipoxygenase (5-LO) catalyzes the two-step conversion of arachidonic acid to LTA4.The first step consists of the oxidation of arachidonic acid to the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), and the second step is the dehydration of 5-HPETE to form LTA4. Leukotriene A4, an unstable epoxide, is hydrolyzed to leukotriene B4 or conjugated with glutathione to yield leukotriene C4 and its metabolites, leukotriene D4 and leukotriene E4. The leukotrienes participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. Recent studies also suggest a neuroendocrine role for leukotriene C4 in luteinizing hormone secretion. (PMID: 10591081, 2820055). Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


12-dehydro-leukotriene B4

12-Keto-leukotriene B4 is formed when leukotriene B4 (LTB4) is metabolized by beta-oxidation. LTB4 is the major metabolite in neutrophil polymorphonuclear leukocytes. Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by beta-oxidation from the w-carboxy position and after CoA ester formation. (PMID: 8632343, 9667737)Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Leukotriene C4

Leukotriene C4 (LTC4) is a cysteinyl leukotriene (CysLT), a family of potent inflammatory mediators. Eosinophils, one of the principal cell types recruited to and activated at sites of allergic inflammation, is capable of elaborating lipid mediators, including leukotrienes derived from the oxidative metabolism of arachidonic acid (AA). Potentially 'activated' eosinophils may elaborate greater quantities of LTC4, than normal eosinophils. These activated eosinophils thus are 'primed' for enhanced LTC4 generation in response to subsequent stimuli. Some recognized priming stimuli are chemoattractants (e.g., eotaxin, PAF) that may participate in the recruitment of eosinophils to sites of allergic inflammation. The mechanisms by which chemoattractants and other activating cytokines (e.g., interleukin (IL)-5) or extracellular matrix components (e.g., fibronectin) enhance eosinophil eicosanoid formation are pertinent to the functions of these eicosanoids as paracrine mediators of allergic inflammation. Some eosinophil-derived eicosanoids may be active in down-regulating inflammation. It is increasingly likely that eicosanoids synthesized within cells, including eosinophils, may have intracellular (e.g., intracrine) roles in regulating cell functions, in addition to the more recognized activities of eicosanoids as paracrine mediators of inflammation. Acting extracellularly, the cysteinyl leukotrienes (CysLTs) LTC4 and its extracellular derivatives, LTD4 and LTE4 are key paracrine mediators pertinent to asthma and allergic diseases. Based on their receptor-mediated capabilities, they can elicit bronchoconstriction, mucous hypersecretion, bronchial hyperresponsiveness, increased microvascular permeability, and additional eosinophil infiltration. Eosinophils are a major source of CysLTs and have been identified as the principal LTC4 synthase expressing cells in bronchial mucosal biopsies of asthmatic subjects. (PMID: 12895596)Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Leukotriene D4

Leukotriene D4 (LTD4) is a cysteinyl leukotriene. Cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. LTD4 is a pro-inflammatory mediator known to mediate its effects through specific cell-surface receptors belonging to the G-protein-coupled receptor family, namely the high-affinity CysLT1 (cysteinyl leukotriene 1) receptor. LTD4 is present at high levels in many inflammatory conditions, and areas of chronic inflammation have an increased risk for subsequent cancer development. LTD4 is associated with the pathogenesis of several inflammatory disorders, such as asthma and inflammatory bowel disease. Exposure to LTD4 increases survival and proliferation in intestinal epithelial cells. CysLT1 regulator is up-regulated in colon cancer tissue and LTD4 signalling facilitates the survival of cancer cells. LTD4 could reduce apoptosis in non-transformed epithelial cells. LTD4 causes up-regulation of beta-catenin through the CysLT1 receptor, PI3K (phosphoinositide 3-kinase), and GSK-3β (glycogen synthase kinase 3β). LTD4 induces beta-catenin translocation to the nucleus and activation of TCF/LEF family of transcription factors. LTD4 causes accumulation of free beta-catenin in non-transformed intestinal epithelial cells through the CysLT1 receptor, and this accumulation is dependent upon the activation of PI3K as well as GSK-3β inactivation (PMID: 16042577, 12607939). Leukotrienes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes), and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent and are able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis through receptor-mediated G-protein linked signaling pathways.


5,6-Ep-15S-hete, also known as 5,6-epoxytetraene, belongs to the class of organic compounds known as fatty alcohols. These are aliphatic alcohols consisting of a chain of a least six carbon atoms. Thus, 5,6-ep-15S-hete is considered to be an eicosanoid lipid molecule. 5,6-Ep-15S-hete is considered to be a practically insoluble (in water) and relatively neutral molecule.


15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HPETE) is the corresponding hydroperoxide of 15(S)-HETE and undergoes homolytic decomposition to the DNA-reactive bifunctional electrophile 4-oxo-2(E)-nonenal, a precursor of heptanone-etheno-2'-deoxyguanosine. Reactive oxygen species convert the omega-6 polyunsaturated fatty acid arachidonic acid into (15-HPETE); vitamin C mediates 15(S)-HPETE decomposition. 15(S)-HPETE initiates apoptosis in vascular smooth muscle cells. 15(S)-HPETE is a lipoxygenase metabolite that affects the expression of cell adhesion molecules (CAMs) involved in the adhesion of leukocytes and/or the accumulation of leukocytes in the vascular endothelium, these being the initial events in endothelial cell injury. 15(S)-HPETE induces a loss of cardiomyocytes membrane integrity. 15-(S)HPETE is a hydroperoxide that enhances the activity of the enzymes lipoxygenase [EC 1.13.11.12] and Na+, K+-ATPase [EC 3.6.3.9] of brain microvessels. Lipoxygenase(s) and Na+-K+-ATPase of brain microvessels may play a significant role in the occurrence of ischemic brain edema. (PMID: 15964853, 15723435, 8655602, 8595608, 2662983).


15(S)-HETE is a hydroxyeicosatetraenoic acid. Hydroxyeicosatetraenoic acids (HETEs) are formed by the 5-, 12- and 15-lipoxygenase (LO) pathways. 5- and 12-LO products are mainly proinflammatory in the skin whereas the main 15-LO product 15-HETE has antiinflammatory capacities. In vitro 15-HETE has been shown to inhibit LTB4 formation, 12-HETE formation and specifically inhibits the neutrophil chemotactic effect of LTB4. The inhibition of LTB4 formation is probably due to modulation of the 5-LO because no changes in PGE2 formation have been determined. In vivo, 15-HETE inhibits LTB4-induced erythema and edema, and reduces LTB4 in the synovial fluid of carragheenan-induced experimental arthritis in dogs. 15-HETE has also some immunomodulatory effects. It inhibits the mixed lymphocyte reaction, induces generation of murine cytotoxic suppressor T cells, and it decreases interferon production by murine lymphoma cells. Furthermore, IL-4 and IL-13 have recently been shown to be potent activators of the 15-LO in mononuclear cells. (PMID: 11104340).


Delta-12-Prostaglandin J2 (d12-PGJ2) is the ultimate metabolite of Prostaglandin D2 (PGD2). PGD2 is an unstable molecule and undergoes dehydration to form PGJ2 in aqueous solution, and is then converted to d12-PGJ2, in the presence of serum albumin or plasma. d12-PGJ2 forms a conjugate with the thiol of glutathione (GSH) and GSH suppresses the d12-PGJ2-induced HSP synthesis and subsequent inhibition of cell growth (HSPs are a set of proteins synthesized in response to heat shock or to other environmental stresses). d12-PGJ2 has been shown to stimulate alkaline phosphatase activity and calcification of human osteoblastic cells, the potency of the PGs being comparable to that of 1-a,25-dihydroxy vitamin D. d12-PGJ2 enhances the type-1 collagen synthesis in human osteoblasts during calcification. Thus, d12-PGJ2 modulates osteogenesis through induction of the syntheses of multiple proteins related to mineralization. Considering that PGD2 is a major arachidonate metabolite in bone marrow, d12-PGJ2, may be physiologically involved in the modulation of osteogenesis. d12-PGJ2 induces heme oxygenase, HO-l. Heme oxygenase is a key enzyme in heme catabolism, oxidatively clearing heme to yield biliverdin, iron and carbon monoxide. The biological function of this enzyme is the conversion of potentially toxic heme to bile and the recovery of the iron. Furthermore, carbon monoxide produced on the enzymatic degradation of heme has been suggested to function as a neural messenger. Two isozymes of heme oxygenase, HO-l and HO-2, have been identified. HO-2 is constitutively expressed, while HO-l is drastically induced in response to a variety of stresses, including heavy metals, heat shock and UV irradiation. (PMID: 8777585)Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


6-oxoprostaglandin F1alpha

6-keto-Prostaglandin F1a is the physiologically active and stable metabolite of prostacyclin. (A prostaglandin found in nearly all mammalian tissue that is a powerful vasodilator and inhibits platelet aggregation; it is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue; the sodium salt has been also used to treat primary pulmonary hypertension (Hypertension, Pulmonary). A delayed and prolonged increase in 6-keto-PGF1 alpha is reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. 6-keto-Prostaglandin F1a plasma levels has been found increased in patients with epidemic hemorrhagic fever, in patients with acute obstructive suppurative cholangitis, in patients with gynecologic cancer and has significant correlation with the level of high density lipoprotein cholesterol in plasma. (PMID 1976492, 2298410, 2379443, 2111556)Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


6-Ketoprostaglandin E1 (6-keto PGE1) is a biologically active and stable prostacyclin (PGI2) metabolite and a substrate for Adenylate cyclase type III. 6-keto PGE1 is a potent coronary vasodilator. 6-keto PGE1 could be elevated in plasma of patients with primary thrombocythaemia. 6-keto-PGE1 has approximately four times less potent antiplatelet activity than PGI2 on a molar basis in man. The cardiovascular and plasma renin activity (PRA) changes are less prominent for 6-keto-PGE1 than PGI2. Salt loading slightly increases urinary 6-keto PGE1. 6-keto-PGE1 elicits the same biological effects as PGI2 in human platelets and in rabbit aorta and mesenteric artery, being, however, less potent. 6-keto-PGE1 dose-dependently stimulates adenylate cyclase activity in membranes of human platelets and cultured myocytes from rabbit aorta and mesenteric artery. The extent of stimulation of the enzyme by 6-keto-PGE1 is the same as elicited by PGI2, while the apparent affinity is lower than that of prostacyclin, both in platelets and in vascular smooth muscle cells. At the level of platelet membranes, 6-keto-PGE1 interacts with the binding sites labelled by PGI2. However, in platelets as well as in mesenteric artery myocytes, 6-keto-PGE1 interacts with only one class of sites as demonstrated either by binding or by adenylate cyclase studies, whereas PGI2 in the same conditions recognizes two different classes. (PMID: 3186779, 3075239, 3472253, 3912001, 3881881, 6391491)Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


5-hydroxyeicosatetraenoic acid (5-HETE) is an endogenous eicosanoid. 5-HETE is an intermediate in arachidonic acid metabolism. It is converted from 5(S)-HPETE via the enzyme glutathione peroxidase (EC 1.11.1.9)and then converted to 5-OxoETE. It is also involved in the pathway of leukotriene synthesis. In addition, it is a modulator of tubuloglomerular feedback.


5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE), 5-lipoxygenase product is a potent chemoattractant for neutrophils and eosinophils. Its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G protein-coupled receptor family.(PMID:18292294).


Prostaglandin J2 (PGJ2) is an endogenous product of inflammation in humans. It induces neuronal death and the accumulation of ubiquitinated proteins into distinct aggregates. It may play a role in neurodegenerative disorders inducing a chain of events that culminates in neuronal cell death. An altered expression of enzymes in PGJ2 synthesis may represent a novel pathogenic mechanism in human obesity. The peroxisome proliferator-activated receptor gamma (PPARγ) has a fundamental role in glucose homeostasis and adipocyte differentiation. Besides linoleate, linolenate and arachidonate, the most notable PPAR ligand is 15-deoxy-delta12-14-prostaglandin J2, a natural derivative of prostaglandin D2 and PGJ2. It is therefore plausible that the production of 15d-PGJ2 within adipose tissue may act as an endogenous mediator of adipocyte differentiation. PGJ2 disrupts the cytoskeleton in neuronal cells. This cyclopentenone prostaglandin triggered endoplasmic reticulum (ER) collapse and the redistribution of ER proteins, such as calnexin and catechol-O-methyltransferase, into a large centrosomal aggregate containing ubiquitinated proteins and alpha-synuclein. The PGJ2-dependent cytoskeletal rearrangement paralleled the development of the large centrosomal aggregate. Supporting a mechanism by which, upon PGJ2 treatment, cytoskeleton/ER collapse coincides with the relocation of ER proteins, other potentially neighboring proteins, and ubiquitinated proteins into centrosomal aggregates. Development of these large perinuclear aggregates is associated with disruption of the microtubule/ER network. This aberrant protein deposition, triggered by a product of inflammation, may be common to other compounds that disrupt microtubules and induce protein aggregation, such as MPP+ and rotenone, found to be associated with neurodegeneration. Many neurodegenerative disorders, such as Parkinson disease, exhibit inclusion bodies containing ubiquitinated proteins. Concentrations of PGJ2 in biofluids have not been established, since this prostaglandin is further metabolized into delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2. (PMID: 16737963, 16842938, 16774923)Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Epoprostenol

Prostaglandin I2 or prostacyclin (or PGI2) is a member of the family of lipid molecules known as eicosanoids. It is produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. It is a powerful vasodilator and inhibits platelet aggregation. Prostaglandin I2 is the main prostaglandin synthesized by the blood vessel wall. This suggests that it may play an important role in limiting platelet-mediated thrombosis. In particular, prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). The sodium salt (known as epoprostenol) has been used to treat primary pulmonary hypertension. Prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels which would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by inhibiting myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as antagonists. PGI2 is stable in basic buffers (pH=8), but it is rapidly hydrolyzed to 6-keto PGF1alpha in neutral or acidic solutions. The half-life is short both in vivo and in vitro, ranging from 30 seconds to a few minutes. PGI2 is administered by continuous infusion in humans for the treatment of idiopathic pulmonary hypertension.Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Prostaglandin D2 (or PGD2) is a prostaglandin that is actively produced in various organs such as the brain, spleen, thymus, bone marrow, uterus, ovary, oviduct, testis, prostate and epididymis, and is involved in many physiological events. PGD2 binds to the prostaglandin D2 receptor (PTGDR) which is a G-protein-coupled receptor. Its activity is mainly mediated by G-S proteins that stimulate adenylate cyclase resulting in an elevation of intracellular cAMP and Ca2+. PGD2 promotes sleep; regulates body temperature, olfactory function, hormone release, and nociception in the central nervous system; prevents platelet aggregation; and induces vasodilation and bronchoconstriction. PGD2 is also released from mast cells as an allergic and inflammatory mediator. Prostaglandin H2 is an unstable intermediate formed from PGG2 by the action of cyclooxygenase (COX) in the arachidonate cascade. In mammalian systems, it is efficiently converted into more stable arachidonate metabolites, such as PGD2, PGE2, PGF2a by the action of three groups of enzymes, PGD synthases (PGDS), PGE synthases and PGF synthases, respectively. PGDS catalyzes the isomerization of PGH2 to PGD2. Two types of PGD2 synthase are known. Lipocalin-type PGD synthase is present in cerebrospinal fluid, seminal plasma and may play an important role in male reproduction. Another PGD synthase, hematopoietic PGD synthase is present in the spleen, fallopian tube, endometrial gland cells, extravillous trophoblasts and villous trophoblasts, and perhaps plays an important role in female reproduction. Recent studies demonstrate that PGD2 is probably involved in multiple aspects of inflammation through its dual receptor systems, DP and CRTH2. (PMID: 12148545)Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Prostaglandin H2 (PGH2) is the first intermediate in the biosynthesis of all prostaglandins. Prostaglandins are synthesized from arachidonic acid by the enzyme COX-1 and COX-2, which are also called PGH synthase 1 and 2. These enzymes generate a reactive intermediate PGH2 which has a reasonably long half-life (90-100 s) but is highly lipophilic. PGH2 is converted into the biologically active prostaglandins by prostaglandin isomerases, yielding PGE2, PGD2, and PGF2, or by thromboxane synthase to make TXA2 or by prostacyclin synthase to make PGI2. Most nonsteroidal anti-inflammatory drugs such as aspirin and indomethacin inhibit both PGH synthase 1 and 2. A key feature for eicosanoid transcellular biosynthesis is the export of PGH2 or LTA4 from the donor cell as well as the uptake of these reactive intermediates by the acceptor cell. Very little is known about either process despite the demonstrated importance of both events. In cells, PGH2 rearranges nonenzymatically to LGs even in the presence of enzymes that use PGH2 as a substrate. When platelets form thromboxane A2 (TXA2) from endogenous arachidonic acid (AA), PGH2 reaches concentrations very similar to those of TXA2 and high enough to produce strong platelet activation. Therefore, platelet activation by TXA2 appears to go along with an activation by PGH2. The agonism of PGH2 is limited by the formation of inhibitory prostaglandins, especially PGD2 at higher concentrations. That is why thromboxane synthase inhibitors in PRP and at a physiological HSA concentration do not augment platelet activation (PMID: 2798452, 15650407, 16968946). Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes), and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent and are able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis through receptor-mediated G-protein linked signalling pathways.


11-epi-PGF2alpha is an intermediate in Arachidonic acid metabolism. 11-epi-PGF2alpha is converted from (5Z,13E)-(15S)-9alpha,15-Dihydroxy-11-oxoprosta-5,13-dienoate via the enzyme prostaglandin-F synthase (EC 1.1.1.188).Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


thromboxane A2

Thromboxane A2 is an unstable intermediate between the prostaglandin endoperoxides and thromboxane B2. The compound has a bicyclic oxaneoxetane structure. It is a potent inducer of platelet aggregation and causes vasoconstriction. It is the principal component of rabbit aorta contracting substance (RCS).Thromboxanes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Dinoprostone

The naturally occurring prostaglandin E2 (PGE2) is known in medicine as dinoprostone, and it is the most common and most biologically active of the mammalian prostaglandins. It has important effects during labour and also stimulates osteoblasts to release factors which stimulate bone resorption by osteoclasts (a type of bone cell that removes bone tissue by removing the bone's mineralized matrix). PGE2 is also the prostaglandin that ultimately induces fever. PGE2 has been shown to increase vasodilation and cAMP production, enhance the effects of bradykinin and histamine, and induce uterine contractions and platelet aggregation. PGE2 is also responsible for maintaining the open passageway of the fetal ductus arteriosus, decreasing T-cell proliferation and lymphocyte migration, and activating the secretion of IL-1α and IL-2. PGE2 exhibits both pro- and anti-inflammatory effects, particularly on dendritic cells (DC). Depending on the nature of maturation signals, PGE2 has different and sometimes opposite effects on DC biology. PGE2 exerts an inhibitory action, reducing the maturation of DC and their ability to present antigen. PGE2 has also been shown to stimulate DC and promote IL-12 production when given in combination with TNF-alpha. PGE2 is an environmentally bioactive substance. Its action is prolonged and sustained by other factors especially IL-10. It modulates the activities of professional DC by acting on their differentiation, maturation, and their ability to secrete cytokines. PGE2 is a potent inducer of IL-10 in bone marrow-derived DC (BM-DC). PGE2-induced IL-10 is a key regulator of the BM-DC pro-inflammatory phenotype (PMID: 16978535). Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes), and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent and are able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis through receptor-mediated G-protein linked signalling pathways.


Dinoprost

Prostaglandin F2a (PGF2) is one of the earliest discovered and most common prostaglandins. It is actively biosynthesized in various organs of mammals and exhibits a variety of biological activities, including contraction of pulmonary arteries. It is used in medicine to induce labor and as an abortifacient. PGF2a binds to the Prostaglandin F2 receptor (PTGFR) which is a member of the G-protein coupled receptor family. PGF2-alpha mediates luteolysis. Luteolysis is the structural and functional degradation of the corpus luteum (CL) that occurs at the end of the luteal phase of both the estrous and menstrual cycles in the absence of pregnancy. PGF2 may also be involved in modulating intraocular pressure and smooth muscle contraction in the uterus and gastrointestinal tract sphincters. PGF2 is mainly synthesized directly from PGH2 by PGH2 9,11-endoperoxide reductase. A small amount of PGF2 is also produced from PGE2 by PGE2 9-ketoreductase. A PGF2 epimer has been reported to exhibit various biological activities, and its levels are increased in bronchoalveolar lavage fluid, plasma, and urine in patients with mastocytosis and bronchial asthma. PGF2 is synthesized from PGD2 by PGD2 11-ketoreductase. (PMID: 16475787). Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Produced by the seminal vesicles, prostaglandins are a group of lipid compounds that are derived enzymatically from fatty acids. Technically hormones, the prostanoid class of fatty acid derivatives is a subclass of eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes), and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis through receptor-mediated G-protein linked signaling pathways. Prostaglandin A is a cyclopentenone and is an endogenous metabolite derived from arachidonic acid. It exhibits potent cellular anti-proliferative activity in vivo and in vitro. Excess PGA2 causes an accumulation in both S and G2/M, and a marked decrease in G1. There is also an increase in DNA content preceeding the G0/G1 peak (indicative of apoptotic body formation) mediated by changes in expression levels of Bax and Bcl-2.


prostaglandin C2

Prostaglandin-C2, also known as PGC2, belongs to the class of organic compounds known as prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid. Thus, prostaglandin-C2 is considered to be an eicosanoid lipid molecule. Prostaglandin-C2 is considered to be a practically insoluble (in water) and relatively neutral molecule. Prostaglandin-C2 has been primarily detected in urine. Within the cell, prostaglandin-C2 is primarily located in the membrane (predicted from logP) and cytoplasm. In humans, prostaglandin-C2 is involved in the nabumetone action pathway, the antrafenine action pathway, the phenylbutazone action pathway, and the trisalicylate-choline action pathway. Prostaglandin-C2 is also involved in a couple of metabolic disorders, which include leukotriene C4 synthesis deficiency and the tiaprofenic Acid action pathway. This compound belongs to the family of Prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.


thromboxane B2

Thromboxanes. A stable, physiologically active compound formed in vivo from the prostaglandin endoperoxides. It is important in the platelet-release reaction (release of ADP and serotonin). -- Pubchem. Thromboxanes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


Prostaglandin B2

Prostaglandin B2 (PGB2) is a prostanoid. Prostanoids is a term that collectively describes prostaglandins, prostacyclines and thromboxanes. Prostanoids are a subclass of the lipid mediator group known as eicosanoids. They derive from C-20 polyunsaturated fatty acids, mainly dihomo-gamma-linoleic (20:3n-6), arachidonic (20:4n-6), and eicosapentaenoic (20:5n-3) acids, through the action of cyclooxygenases-1 and -2 (COX-1 and COX-2). The reaction product of COX is the unstable endoperoxide prostaglandin H (PGH) that is further transformed into the individual prostanoids by a series of specific prostanoid synthases. Prostanoids are local-acting mediators formed and inactivated within the same or neighbouring cells prior to their release into circulation as inactive metabolites (15-keto- and 13,14-dihydroketo metabolites). Non-enzymatic peroxidation of arachidonic acid and other fatty acids in vivo can result in prostaglandin-like substances isomeric to the COX-derived prostaglandins that are termed isoprostanes. Prostanoids take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. Their activities are mediated through prostanoid-specific receptors and intracellular signalling pathways, whilst their biosynthesis and action are blocked by nonsteroidal antiinflammatory drugs (NSAID). Isoprostanes are considered to be reliable markers of oxidant stress status and have been linked to inflammation, ischaemia-reperfusion, diabetes, cardiovascular disease, reproductive disorders and diabetes. (PMID: 16986207). Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


11-Dehydro-thromboxane B2, a stable thromboxane metabolite, is a full agonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) in human eosinophils and basophils. Given its production in the allergic lung, antagonism of the 11-dehydro- thromboxane B2/CRTH2axis may be of therapeutic relevance. (PMID 14668348)Thromboxanes are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.


11H-14,15-EETA is an epoxyeicosatrienoic acid. Epoxyeicosatrienoic acids (EpETrEs) have been reported recently having vasodilatory effects and a role of P-450-dependent arachidonic acid monooxygenase metabolites is suggested in vasoregulation. The physiological role of this compound has not been totally established, although in other tissues EpETrEs are mainly involved in hormone production and in the vascular and renal systems. Some studies have implicated epoxygenase metabolites of arachidonic acid in the control of steroidogenesis in luteinised granulosa cells. (PMID: 12749593, 12361727, 1650001).


11,14,15-trihydroxyeicosatrienoic acid (11,14,15-THETA) is a metabolite of the 15-lipoxygenase (15-LO) pathway of arachidonic acid (AA). Increased amounts of 11,14,15-THETA are synthesized in subacute hypoxia. Prolonged exposure to reduced PO2 activates 15-LO in small pulmonary arteries (PA); activation of 15-LO is associated with translocation of the enzyme from the cytosol to membrane. 11,14,15-THETA is an endothelium-derived relaxing factor. (PMID: 12690037, 9812980, 15388505, 14622984).


15H-11,12-EETA is an epoxyeicosatrienoic acid (EET). The role of EETs in regulation of the cerebral circulation has become more important, since it was realized that EETs are produced in another specialized cell type of the brain, the astrocytes. It has become evident that EETs released from astrocytes may mediate cerebral functional hyperemia. Molecular and pharmacological evidence hve shown that neurotransmitter release and spillover onto astrocytes can generate EETs. Since these EETs may reach the vasculature via astrocyte foot-processes, they have the same potential as their endothelial counterparts to hyperpolarize and dilate cerebral vessels. P450 enzymes contain heme in their catalytic domain and nitric oxide (NO) appears to bind to these heme moieties and block formation of P450 products, including EETs. Thus, there appears to be crosstalk between P450 enzymes and NO/NO synthase. The role of fatty acid metabolites and cerebral blood flow becomes even more complex in light of data demonstrating that cyclooxygenase products can act as substrates for P450 enzymes. (PMID: 17494091, 17468203, 17434916, 17406062, 17361113, 15581597, 11413051, 10519554, 11893556).


11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA) is a metabolite of the 15-lipoxygenase (15-LO) pathway of arachidonic acid (AA). 11,12,15-THETA is an endothelium-derived relaxing factor. Acetylcholine stimulates AA release from membrane phospholipids of vascular endothelial cells (ECs). AA is released from phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by phospholipase A2 (PLA2), or from phosphatidylinositol (PI) by phospholipase C (PLC) pathway. The diacylglycerol (DAG) lipase can convert DAG into 2-arachidonoylglycerol from which free AA can be released by monoacylglycerol (MAG) lipase or fatty acid amidohydrolase (FAAH). 11,12,15-THETA mediates the acetylcholine-induced vaso-relaxation, via activation of the K+ channels to hyperpolarize the smooth muscle membrane and induce relaxation. (PMID: 12907422, 16024567, 15388505, 14622984).


16(R)-HETE is a metabolite of arachidonic acid, metabolized by the enzyme Cytochrome P450, family 2, subfamily C [EC:1.14.13.80 1.14.13.48 1.14.13.49]. 16(R)-HETE is an endogenous lipidic inhibitor of human neutrophil inhibitor of adhesion and aggregation activity. Human polymorphonuclear leukocytes (PMNs) produce 16(R)-HETE that modulates their function. HETEs have different biological properties based on sites of production and can be stored in tissue lipids and released in response to hormonal stimuli. Eicosanoids generated during the actions of growth factors and vasoconstrictors can modulate disease processes by affecting vascular homeostasis, inflammation, cellular growth, apoptosis and oxidant stress. In lung, the presence of these eicosanoids in the pulmonary vasculature and airways, including effects on pulmonary vascular and bronchial smooth muscle tone and airway epithelial ion transport. (PMID: 16258232, 14626496, 12681244, 11123211, 14552765, 11126912).


14,15-epoxy-5,8,11-eicosatrienoic acid is an epoxyeicosatrienoic acid (EET), a metabolite of arachidonic acid. The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced by P450 epoxygenases and metabolized through multiple pathways including soluble epoxide hydrolase (sEH). The cytochrome P-450 (P450) monooxygenase pathway includes enzymes of the CYP1A, CYP2B, CYP2C, CYP2E, and CYP2J subfamilies that catalyze the formation of four regioisomeric products, 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid. EETs are produced in brain and perform important biological functions, including protection from ischemic injury. Both light flashes and direct glial stimulation produce vasodilatation mediated by EETs. EETs may be involved in the development of hypertension and endothelial dysfunction in DOCA-salt rats, but not in excessive collagen deposition or electrophysiological abnormalities. EETs have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Four regioisomeric cis-EET are primary products of arachidonic acid metabolism by cytochrome P450 epoxygenases. Upon hydration by soluble epoxide hydrolase (sEH), EET are metabolized to dihydroxyeicosatrienoic acids (DHET). These hydration products are more stable and less biologically active than EETs. (PMID: 17494091, 17468203, 17434916, 17406062, 17361113, 15581597).


14,15-DiHETrE is a Cytochrome P450 (P450) eicosanoid. Eicosanoids generated from arachidonic acid metabolism by cytochrome P450 (P450) enzymes are important autocrine and paracrine factors that have diverse biological functions. P450 eicosanoids are involved in the regulation of vascular tone, renal tubular transport, cardiac contractility, cellular proliferation, and inflammation. Regulation of P450 eicosanoid levels is determined by many factors, including the induction or repression of the P450 enzymes responsible for their formation. Fibrate drugs are part of a diverse group of compounds known as peroxisome proliferators, which also include herbicides and phthalate ester plasticizers. Peroxisome proliferators act via peroxisome proliferator-activated receptor (PPAR ). This receptor is a member of the PPAR nuclear receptor family that also consists of the PPAR and PPAR isoforms. PPAR is mainly expressed in the heart, liver, and kidney, whereas the expression of PPAR is predominantly in the adipose tissue. The biological role of PPAR as a lipid sensor has been well established. 14,15-DiHETrE is a potent activators of PPAR and PPAR, shown to induce the binding of PPAR to a peroxisome proliferator response element (PPRE). Furthermore, 14,15-DiHETrE behaves like peroxisome proliferators in that is able to alter apoA-I and apoA-II mRNA expression. 14,15-DiHETrE is the most potent PPARalpha activator in a COS-7 cell expression system producing a 12-fold increase in PPARalpha-mediated luciferase activity. (PMID: 17431031, 16113065).


11,12-Epoxyeicosatrienoic acid is an epoxyeicosatrienoic acid (EET). Induction of CYP2C8 in native coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as endothelium-derived hyperpolarizing factor-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP2C8 antisense oligonucleotides resulted in decreased levels of CYP2C and attenuated the endothelium-derived hyperpolarizing factor-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of the endothelium-derived hyperpolarizing factor-mediated relaxation in the porcine coronary artery, and CYP2C8 fulfills the criteria for the coronary endothelium-derived hyperpolarization factor synthase. The role of EETs in regulation of the cerebral circulation has become more important, since it was realized that EETs are produced in another specialized cell type of the brain, the astrocytes. It has become evident that EETs released from astrocytes may mediate cerebral functional hyperemia. Molecular and pharmacological evidence hve shown that neurotransmitter release and spillover onto astrocytes can generate EETs. Since these EETs may reach the vasculature via astrocyte foot-processes, they have the same potential as their endothelial counterparts to hyperpolarize and dilate cerebral vessels. P450 enzymes contain heme in their catalytic domain and nitric oxide (NO) appears to bind to these heme moieties and block formation of P450 products, including EETs. Thus, there appears to be crosstalk between P450 enzymes and NO/NO synthase. The role of fatty acid metabolites and cerebral blood flow becomes even more complex in light of data demonstrating that cyclooxygenase products can act as substrates for P450 enzymes. (PMID: 17494091, 17468203, 17434916, 17406062, 17361113, 15581597, 11413051, 10519554).


11,12-DiHETrE is a Cytochrome P450 (P450) eicosanoid. Arachidonic acid may be oxygenated by cytochrome P450 in several ways. Epoxidation of the double bonds leads to the regio- and enantioselective formation of four epoxyeicosatrienoic acids (EETs), which are hydrolyzed by epoxide hydrolase to vicinal diols (DHETs). 11,12-DiHETrE excretion is increased in healthy pregnant women compared with nonpregnant female volunteers, and increased even further in patients with pregnancy-induced hypertension (PIH). The physiological significance of arachidonic acid epoxides has been debated and it is unknown whether they play a role in pregnancy and parturition. Vasodilative effects, inhibition of cyclooxygenase, or inhibition of platelet aggregation by EETs have been observed only at micromolar concentrations. On the other hand, effects on the stimulus-secretion coupling during hormone release have been found in the nanomolar and picomolar range. (PMID: 9440131, 2198572).


5-HPETE, also known as 5(S)-hpete, belongs to the class of organic compounds known as hydroperoxyeicosatetraenoic acids. These are eicosanoic acids with an attached hydroperoxyl group and four CC double bonds. Thus, 5-hpete is considered to be an eicosanoid lipid molecule. 5-HPETE is considered to be a practically insoluble (in water) and relatively neutral molecule. 5-HPETE has been primarily detected in urine. Within the cell, 5-hpete is primarily located in the membrane (predicted from logP) and cytoplasm. In humans, 5-hpete is involved in the salicylate-sodium action pathway, the lornoxicam action pathway, the bromfenac action pathway, and the suprofen action pathway. 5-HPETE is also involved in a couple of metabolic disorders, which include the tiaprofenic Acid action pathway and leukotriene C4 synthesis deficiency. Arachidonic acid 5-hydroperoxide (5-hydroperoxyeicosatetraenoic acid, 5-HPETE) is an intermediate in the production of leukotriene A4 from arachidonic acid.


Prostaglandin G2 (PGG2) is synthesized from arachidonic acid on a cyclooxygenase (COX) metabolic pathway as a primary step; the COX biosynthesis of prostaglandin (PG) begins with the highly specific oxygenation of arachidonic acid in the 11R configuration and ends with a 15S oxygenation to form PGG2. The COX site activity that catalyzes the conversion of arachidonic acid to PGG2 is the target for nonsteroidal antiinflammatory drugs (NSAIDs). The peroxidase site activity catalyzes the two-electron reduction of the hydroperoxide bond of PGG2 to yield the corresponding alcohol prostaglandin H2 (PGH2). The formation of a phenoxyl radical on Tyr385 couples the activities of the two sites. The Tyr385 radical is produced via oxidation by compound I, an oxoferryl porphyrin -cation radical, which is generated by reaction of the hemin resting state with PGG2 or other hydroperoxides. The tyrosyl radical homolytically abstracts the 13proS hydrogen atom of arachidonic acid which initiates a radical cascade that ends with the stereoselective formation of PGG2. PGG2 then migrates from the cyclooxygenase (COX) site to the peroxidase (POX) site where it reacts with the hemin group to generate PGH2 and compound I. The heterolytic oxygen-oxygen bond cleavage is assisted by the conserved distal residues His207 and Gln203, mutation of which has been shown to severely impair enzyme activity. Compound I, upon reaction with Tyr385, gives compound II, which in turn is reduced to the hemin resting state by one-electron oxidation of reducing cosubstrates or undergoes reactions that result in enzyme self-inactivation. Prostaglandin endoperoxide H synthase (PGHS) 1 is a bifunctional membrane enzyme of the endoplasmic reticulum that converts arachidonic acid into prostaglandin H2 (PGH2), the precursor of all prostaglandins, thromboxanes, and prostacyclins. These lipid mediators are intricately involved in normal physiology, namely, in mitogenesis, fever generation, pain response, lymphocyte chemotaxis, fertility, and contradictory stimuli such as vasoconstriction and vasodilatation, as well as platelet aggregation and quiescence. PGHS is implicated in numerous pathologies, including inflammation, cancers of the colon, lung, and breast, Alzheimer's disease, Parkinson's disease, and numerous cardiovascular diseases including atherosclerosis, thrombosis, myocardial infarction, and stroke. (PMID: 14594816, 16552393, 16411757). Prostaglandins are eicosanoids. The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and lipoxins (LXs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.