Pathways

Creatine is a nitrogenous low-molecular-weight water-soluble organic acid mostly stored in muscle. Mammals get creatine from their diet - meat, fish, and supplements contain L-arginine (an essential amino acid), among other amino acids such as glycine and S-adenosyl-L-methionine, which are involved in energy transfer via phosphocreatine. These can be metabolized to creatine before excretion through the kidney. After arginine enters the body, it is absorbed in the intestinal epithelium to the bloodstream and transported to the liver via an amino acid transporter where it undergoes two metabolic reactions. First, arginine is used to form guanidinoacetic acid in a reaction catalysed by glycine amidinotransferase, then that product undergoes a reaction catalysed by guanidinoacetate N-methyltransferase to form creatine. Creatine then exits the hepatocyte and enters the blood via a sodium- and chloride-dependent creatine transporter; here, it can induce systemic oxidative stress and lead to the toxic effect of cell death.

Creatinine is a low-molecular-weight uremic solute and breakdown product of creatine phosphate in muscle, often used as a clinical marker of renal function (altered serum creatinine clearance levels can indicate pathophysiology in various diseases). Arginine from the diet is absorbed into systemic circulation and enters hepatocytes through an amino acid transporter, where it undergoes a series of metabolic reactions. First, it forms guanidinoacetic acid in a reaction catalysed by glycine amidinotransferase, then undergoes a reaction catalysed by guanidinoacetate N-methyltransferase to form creatine. Creatine is non-enzymatically converted into creatinine, which can exit the liver via the solute carrier family 22 member 2 transporter to enter the bloodstream. If not cleared, it can reduce cardiomyocyte contractility and weaken cardiac efficiency, leading to systolic dysfunction and heart failure.

Dimethylglycine (DMG) is an amino acid derivative found in the cells of all plants and animals and can be obtained in the diet in small amounts from grains and meat. The human body produces DMG when metabolizing choline into glycine. Choline is obtained from dietary sources like meat, fish, eggs and poultry. Choline is metabolized in the liver to betaine aldehyde in the mitochondria via the enzyme choline dehydrogenase. Betaine aldehyde is the converted to betaine through alpha-aminoadipic semialdehyde dehydrogenase. Finally, betaine--homocysteine S-methyltransferase 1 produces dimethylglycine from betaine. Dimethylglycine enters the bloodstream and can cause toxic effects on the cardiovascular system.

Hippuric acid is an acyl glycine present in normal urine. This uremic toxin’s presence increases with consumption of phenol-rich foods (e.g. tea, wine, fruit juice, etc.). Polyphenols are converted into benzoic acid, which then follows the illustrated pathway. Also (as shown), certain foods are rich in benzoic acid - whether naturally, e..g cheese ripening process, whole-grains, or artificially enriched e.g. use of a benzoic acid salt preservative. After ingestion and absorption in the gut, benzoic acid is transported into the hepatic liver cell from blood where it undergoes two metabolic reactions. First, benzoic acid is converted into benzoyl-coenzyme A (BCoA) in a reaction catalysed by acyl-coenzyme A synthetase, then BCoA forms hippuric acid in a conjugation reaction catalysed by the glycine N-acetyltransferase enzyme. A monocarboxylate transporter then exports hippuric acid from the liver to the blood, where it exerts toxic effects. It can reduce blood clotting and, in the kidney, inhibit organic acid secretion. It is associated with phenylketonuria, propionic acidemia, and tyrosinemia I (genetic metabolic disorders).

Homocysteine is an amino acid that, in humans, is elevated in vitamin and folate deficiency. It is also a uremic toxin and modifiable risk factor for cardiovascular disorder. Foods rich in methionine (e.g. meat, eggs) are digested and produce homocysteine. After intestinal absorption and entry into the bloodstream, methionine is transported to the hepatocyte where it undergoes three metabolic reactions. First, in a reaction catalysed by methionine adenosyltransferase, methionine reacts with ATP and water to form S-adenosylmethionine with phosphate and pyrophosphate byproducts. Then, S-adenosylmethionine forms S-adenosylhomocysteine in a reaction catalysed by dimethyladenosine transferase. Finally, S-adenosylhomocysteine is used with water to form homocysteine in a reaction catalysed by adenosylhomocysteinase with an adenosine byproduct. Homocysteine enters systemic circulation via an amino acid transporter where it then induces oxidative stress, which can lead to cell death. Though the mechanism is unclear, homocysteine is associated with Alzheimer’s disease and cardiovascular disorder, namely atherosclerosis.

Imidazolepropionic acid, also known as deaminohistidine or 4-imidazolylpropionate (ImP), 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. ImP is a metabolite of histidine and it is formed from histidine via a urocanate intermediate in gut microbiota by the enzyme urocanate reductase (urdA). Histidine can be obtained from the diet from foods such as meat and dairy and other foods high in protein. ImP is a very strong basic compound (based on its pKa). ImP is a product of histidine metabolism which may involve oxidation or transamination. Imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).

Indole acetic acid is an indole compound that is formed through gut microbial metabolism from dietary tryptophan through the indole-3-acetamide pathway . After being transported into gut microbes, tryptophan undergoes a reaction with the enzymes tryptophan monooxygenase and indole-3-acetamide hydrolase to form indole acetic acid. Indole acetic acid that is produced from the gut microbes then enters systemic circulation. This compound is shown to be a uremic toxin through high levels of retention. Indole acetic acid is shown to cause inflammation and disrupt the electron transport chain and oxidative phosphorylation causing muscle atrophy.

Indoleacetyl glutamine is indolic derivative of tryptophan. It is generated from indoleacetic acid. Indoleacetic acid (IAA) is a breakdown product of tryptophan metabolism and is often produced by the action of bacteria in the mammalian gut. Some endogenous production of IAA in mammalian tissues also occurs. It may be produced by the decarboxylation of tryptamine or the oxidative deamination of tryptophan. Indoleacetyl glutamine frequently occurs at low levels in urine and has been found in elevated levels in the urine of patients with hartnup disease, the characteristic symptoms of the disease are mental retardation and pellagra like skin rash. Several intestinal bacteria, such as Bacteroides, Clostridia, and E. coli, can catabolize Trp to tryptamine and indole pyruvic acid, which are then converted to indole-3-acetic acid, indole propionic acid, and indole lactic acid. Indole-3-acetic acid can be further combined with glutamine to produce indolyl acetyl glutamine in the liver or oxidized to indole-3-aldehyde (IAld) through peroxidase-catalyzed aerobic oxidation.

Indolelactic acid (CAS: 1821-52-9) is a tryptophan metabolite found in human plasma, serum, and urine. Tryptophan is metabolized by two major pathways in humans, either through kynurenine or via a series of indoles, and some of its metabolites are known to be biologically active. Indolelactic acid is present in various amounts, significantly higher in umbilical fetal plasma than in maternal plasma in the protein-bound form. Indolelactic acid is also a microbial metabolite; urinary indole-3-lactate is produced by Clostridium sporogenes.Phenylalanine, tyrosine and tryptophan are all metabolized through the reductive pathway by the same enzymes. The first step is an aminotransferase reaction, probably catalysed by aromatic amino acid aminotransferase (Aat). The enzyme involved in indoleacetic acid production remains unknown, however, candidate genes in the genome include pyruvate:ferredoxin oxidoreductases B and C (PorB, CLOSPO_02262; PorC, CLOSPO_03792).

Indoxyl glucoside (indican) is an indole compound that is formed through gut microbial metabolism from dietary tryptophan and a sulfation reaction in liver hepatic cells. After being transported into gut microbes, tryptophan undergoes a reaction with the enzyme tryptophanase to form indole. Indole that is produced from the gut microbes then enters systemic circulation. Following this absorption, indole is transported to the liver where it forms 3-hydroxyindole (indoxyl or indican) in a reaction catalysed by the cytochrome P450 2E1 enzyme. Indican, when oxidized, turns blue. Ultimately this compound undergoes sulfation or glucuronidation as a normal xenobiotic metabolite before being excreted by the kidneys. It is a uremic toxin as identified by the European Uremic Toxin Working Group and accumulates in the presence of Lactobacillus bacteria in the gut. It is found in individuals affected by the blue diaper syndrome (a rare, autosomal recessive metabolic disorder characterized in infants by bluish urine-stained diapers), the patients exhibit a defect in tryptophan metabolism, leading to an increase in indican synthesis. Indican is then excreted into the urine and from there into the diaper where, upon exposure to air, it is converted to indigo blue dye due to oxidation by atmospheric oxygen. An increased urinary excretion of indican is seen in Hartnup disease from the bacterial degradation of unabsorbed tryptophan. Hartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan), which leads to excessive bacterial fermentation of tryptophan (to indole) in the gut. It exerts toxic effects when it forms indoxyl sulfate. As such, it reduces Erythropoetin production which ultimately results in renal anemia. It is also shown to cause vascular calcification and disrupt the electron transport chain and oxidative phosphorylation causing muscle atrophy.