Pathways

Phenyl glucuronide is a phenolic compound that is formed through gut microbial metabolism from dietary tyrosine and a glucuronidation reaction in liver hepatic cells. After being transported into gut microbes, tyrosine undergoes a reaction with the enzyme tyrosine phenol-lyase to form phenol. Phenol that is produced from the gut microbes then enters systemic circulation. Ultimately phenol undergoes a reaction in a liver hepatocyte through a glucuronosyltransferase enzyme to form Phenyl glucuronide. When this compound returns back into systemic circulation it is shown to be a major uremic toxin through high levels of retention. Phenyl glucuronide is shown to

Phenyl sulphate is a phenolic compound that is formed through gut microbial metabolism from dietary tyrosine and a sulfation reaction in liver hepatic cells. After being transported into gut microbes, tyrosine undergoes a reaction with the enzyme tyrosine phenol-lyase to form phenol. Phenol that is produced from the gut microbes then enters systemic circulation. Ultimately phenol undergoes a sulfation reaction in a liver hepatocyte through a sulfotransferase enzyme to form Phenyl sulphate. When Phenyl sulphate returns back into systemic circulation it is shown to be a major uremic toxin through high levels of retention. Phenyl sulphate is shown to cause albuminuria and diabetic kidney disease.

Phenylacetic acid is carboxylic acid ester that has also been found to be a uremic toxin that is synthesized from L-phenylalanine. L-Phenylalanine is consumed through high protein foods such as eggs, chicken, liver, beef, milk, and soybeans. In the intestine L-phenylalanine is converted into 2-phenylethylamine by the enzyme Aromatic-L-amino-acid decarboxylase. 2-Phenylethylamine then is transported into the periplasm of intestinal bacteria such as E. Coli strain K12 through an unknown transporter. In the periplasm of the E. coli, 2-phenylethylamine is catalyzed by the enzyme primary amine oxidase to synthesize phenylacetaldehyde. Phenylacetaldehyde is transported into the cytosol of the E. coli bacteria where it is catalyzed by the enzyme phenylacetaldehyde dehydrogenase to synthesize phenylacetic acid. Phenylacetic acid is transported out of the bacteria, back into the intestine by an unknown transporter. Phenylacetic acid is then transported into the blood where it has various effects on the human body. It reduces nitric oxide production and reduces protection against inflammation in vessel walls. It also leads to the production of reactive oxygen species. It also contribute to inflammation by priming polymorphonuclear leucocytes.

Phenylacetylglutamine is a product formed by the conjugation of phenylacetate and glutamine. It is a common metabolite that occurs naturally in human urine. The highly-nitrogenous compound is most commonly encountered in human subjects with urea cycle disorders,. These conditions, such as uremia or hyperammonemia, tend to cause high levels of nitrogen in the form of ammonia in the blood. Uremic conditions are a result of defects in enzymes that convert ammonia to urea, the primary nitrogenous waste metabolite in the urea cycle. Phenylacetylglutamine is a product formed from the conjugation of phenylacetate and glutamine. Technically, it is the amino acid acetylation product of phenylacetate (or phenylbutyrate after beta-oxidation). Phenylacetylglutamine is a normal constituent of human urine, but other mammals such as the dog, cat, rat, monkey, sheep, and horse do not excrete this compound. Phenylacetyl-CoA and L-glutamine react to form phenylacetylglutamine and coenzyme A. The enzyme (glutamine N-acetyl transferase) that catalyzes this reaction has been purified from human liver mitochondria and shown to be a polypeptide species distinct from glycine-N-acyltransferase. Phenylacetylglutamine is a major nitrogenous metabolite that accumulates in uremia. It has been shown that over 50% of urine phenylacetylglutamine may be derived from kidney conjugation of free plasma phenylacetic acid and/or from the kidney's preferential filtration of conjugated phenylacetic acid. Phenylacetylglutamine is a microbial metabolite found in Christensenellaceae, Lachnospiraceae and Ruminococcaceae.

Phenylacetylglycine is an acyl glycine. Acyl glycines are normally minor metabolites of fatty acids. However, the excretion of certain acyl glycines is increased in several inborn errors of metabolism. In certain cases the measurement of these metabolites in body fluids can be used to diagnose disorders associated with mitochondrial fatty acid beta-oxidation. Acyl glycines are produced through the action of glycine N-acyltransferase (EC 2.3.1.13) which is an enzyme that catalyzes the chemical reaction:. acyl-CoA + glycine < -- > CoA + N-acylglycine. Phenylacetylglycine or PAG is a glycine conjugate of phenylacetic acid. Phenylacetic acid may arise from exposure to styrene (plastic) or through the consumption of fruits and vegetables. Phenylacetic acid is used in some perfumes, possessing a honey-like odour in low concentrations, and is also used in penicillin G production. PAG is a putative biomarker of phospholipidosis. Urinary PAG is elevated in animals exhibiting abnormal phospholipid accumulation in many tissues and may thus be useful as a surrogate biomarker for phospholipidosis. The presence of phenylacetylglycine in urine has been confirmed for dogs, rats and mice. However, the presence of this compound in human urine is controversial. GC-MS studies have not found this compound, while NMR studies claimed to have identified it. Glycine N-Phenylacetyltransferase is a mitochondrial acyltransferase which transfers the acyl group to the N-terminus of glycine (glycine + phenylacetyl-CoA = CoA + H+ + phenylacetylglycine). Can conjugate a multitude of substrates to form a variety of N-acylglycines. Phenylacetyl-CoA comes from the metabolism of phenylalanine.

Putrescine is an aliphatic amine that is formed through gut microbial metabolism from the amino acid arginine which is acquired from foods that are high in protein. After being transported into gut microbes, arginine undergoes 2 reactions with the enzymes Arginase and Ornithine Decarboxylase to form putrescine. Like other polyamines such as spermidine and spermine, putrescine can also be obtained directly from diet as well. While putrescine is important for interactions and processes involving, DNA, RNA and proteins, at high levels it is also a protein bound uremic toxin found in the body that can inhibit erythropoietin production which can eventually lead to anemia.

Quinolinic acid is an indole uremic toxin compound that is formed through metabolism from dietary tryptophan in liver hepatic cells. After being transported into a hepatocyte from portal circulation the amino acid tryptophan undergoes a multi-step reaction with the enzymes tryptophan-2,3-dioxygenase, kynurenine 3-monooxygenase, kynureninase, and 3-hydroxyanthranilate 3,4-dioxygenase to form quinolinic acid. When this compound enters into systemic circulation it is shown to be a major uremic toxin when high levels of it are retained in the blood and not excreted in urine. Quinolinic acid is shown to have major neurotoxic effects on the brain by acting as an NMDA receptor agonist, causing excessive glutamate release and lipid peroxidation.

S-Adenosyl-L-homocysteine (SAH) is formed by the demethylation of S-adenosyl-L-methionine. S-Adenosylhomocysteine (AdoHcy or SAH) is also the immediate precursor of all of the homocysteine produced in the body. The reaction is catalyzed by S-adenosylhomocysteine hydrolase and is reversible with the equilibrium favoring formation of SAH. In vivo, the reaction is driven in the direction of homocysteine formation by the action of the enzyme adenosine deaminase which converts the second product of the S-adenosylhomocysteine hydrolase reaction, adenosine, to inosine. Except for methyl transfer from betaine and from methylcobalamin in the methionine synthase reaction, SAH is the product of all methylation reactions that involve S-adenosylmethionine (SAM) as the methyl donor. Methylation is significant in epigenetic regulation of protein expression via DNA and histone methylation. The inhibition of these SAM-mediated processes by SAH is a proven mechanism for metabolic alteration. Because the conversion of SAH to homocysteine is reversible, with the equilibrium favoring the formation of SAH, increases in plasma homocysteine are accompanied by an elevation of SAH in most cases. Disturbances in the transmethylation pathway indicated by abnormal SAH, SAM, or their ratio have been reported in many neurodegenerative diseases, such as dementia, depression, and Parkinson's disease. Therefore, when present in sufficiently high levels, S-adenosylhomocysteine can act as an immunotoxin and a metabotoxin. An immunotoxin disrupts, limits the function, or destroys immune cells. A metabotoxin is an endogenous metabolite that causes adverse health effects at chronically high levels. Chronically high levels of S-adenosylhomocysteine are associated with S-adenosylhomocysteine (SAH) hydrolase deficiency and adenosine deaminase deficiency. S-Adenosylhomocysteine forms when there are elevated levels of homocysteine and adenosine. S-Adenosyl-L-homocysteine is a potent inhibitor of S-adenosyl-L-methionine-dependent methylation reactions. It is toxic to immature lymphocytes and can lead to immunosuppression. Methionine can be obtained from foods such as meat, eggs, dairy products, and nuts and is converted to adenosylmethionine which is then further converted to adenosylhomocysteine in the hepatocytes of the liver.

Spermidine is an aliphatic amine that is formed through gut microbial metabolism from the amino acid arginine which is acquired from foods that are high in protein. After being transported into gut microbes, arginine undergoes 2 reactions with the enzymes Arginase and Ornithine Decarboxylase to first form the polyamine putrescine. Then putrescine undergoes a further reaction involving the enzyme spermidine synthase to form spermidine. Like other polyamines, spermidine can also be obtained directly from diet as well. While spermidine can be beneficial and act as a scavenger of reactive oxygen species protecting DNA from oxidative damage, at high levels it is also a protein bound uremic toxin found in the body that can inhibit erythropoietin production eventually leading to anemia.