Pathways

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.

Spermine 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. Putrescine undergoes a further reaction involving the enzyme spermidine synthase to form spermidine which ultimately forms spermine with the help of the enzyme spermine synthase. Like other polyamines, spermine can also be obtained directly from diet as well. While spermine 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.

Symmetrical dimethylarginine (SDMA) is produced from L-arginine. L-arginine is obtained from protein-rich foods like red meat, poultry, dairy and eggs. It is absorbed in the intestine to the blood. It enters cells in the body and is metabolized to SDMA via the enzyme protein arginine methyltransferase-5 or protein arginine methyltransferase-7. SDMA is considered a uremic toxin because it contributes chronic kidney disease by acting as a proinflammatory agent. SDMA produces activation of NFκB with enhanced expression of inflammatory cytokines. It also modifies high-density lipoprotein (HDL), inducing endothelial damage and increase monocytic reactive oxygen species (ROS) production, which also causes vascular damage. Therefore, SDMA also contributes to cardiovascular diseases.

Tiglylglycine 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. Tiglylglycine is an intermediate product of the catabolism of isoleucine. An elevated level of tiglylglycine is identified in urine of patients with beta-ketothiolase deficiency or with disorders of propionate metabolism. Tiglyglycine is a biomarker for the consumption of cheese. Tiglyglycine (TG), an intermediate product of the catabolism of isoleucine, is increased in the urine of patients with beta-ketothiolase deficiency or with disorders of propionate metabolism. It is also implicated as a useful diagnostic marker in disorders of the respiratory chain. In the mitochondria, isoleucine is converted to 2-oxo-3-methylvaleric acid vis a transaminase. This is then converted into 2-methylbutyryl-CoA by the BCKADH complex. This is then converted to tiglyl-CoA by SBCAD which can then be made into tiglylglycine via glycine N-acyltransferase.