Pathways

O-Sulfotyrosine belongs to the class of organic compounds known as phenylalanine and derivatives. Phenylalanine and derivatives are compounds containing phenylalanine or a derivative thereof resulting from a reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom. O-Sulfotyrosine has been identified as a potential plasma biomarker of reduced kidney function in early chronic kidney disease (CKD), end stage renal disease (ESRD), and hemodialytic clearance. Human plasma levels of O-sulfotyrosine were reported to be influenced by genetic variants in the gene ARSA which codes for the enzyme arylsulfatase A. Tyrosine sulfation is a posttranslational modification where a sulfate group is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi apparatus may be sulfated. Sulfation is catalyzed by tyrosylprotein sulfotransferase (TPST) in the Golgi apparatus.

Orotic acid (orotate) is classified as a pyrimidinemonocarboxylic acid. Most urinary orotic acid is synthesized in the body, where it arises as an intermediate in the pathway for the synthesis of pyrimidine nucleotides. It originates from l-glutamine, which is obtained from protein sources such as red meat and eggs in the diet. L-glutamine is metabolized to orotate in the liver. L-glutamine is first converted to carbamoyl phosphate then to N-Carbamoyl-L-aspartate and finally to dihydroorotate by the CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). Dihydroorotate is converted to orotate in the mitochondria of the cell via the enzyme dihydroorotate dehydrogenase. Orotate can enter the bloodstream where it exerts detrimental effects on other systems. A build up of orotate in the body leads to acidosis which can have detrimental effects on other systems in the body causing renal failure, neurotoxicity, endothelial dysfunction and hypertension.

Oxalic acid (oxalate) is a strong dicarboxylic acid that is also a known uremic toxin. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid. Glyoxylate is generated through glycine and hydroxyproline catabolism and can be converted to oxalate. In humans, this process takes place in the liver. Glycine and hydroxyproline comes from protein sources in the diet such as red meat and eggs. Glycine Is converted into glyoxylate in the peroxisome by the enzyme d-amino acid oxidase. Proline is converted to hydroxyproline in the endoplasmic reticulum using the enzyme prolyl 4-hydroxylase. The hydroxyproline metabolism to glyoxylate occurs in the mitochondria. Hydroxyproline dehydrogenase converts hydroxyproline to pyrroline hydroxycarboxylic acid. Delta-1-pyrroline-5-carboxylate dehydrogenase then catalyzes the formation of 4-hydroxy-L-glutamic acid from pyrroline hydroxycarboxylic acid. 4-hydroxy-2-oxoglutaric acid is then produced from 4-hydroxy-L-glutamic acid using the enzyme aspartate aminotransferase. Finally, 4-hydroxy-L-glutamic acid is converted to glyoxylate using 4-hydroxy-2-oxoglutarate aldolase. The glyoxylate formed enters the cytosol. in the cytosol, glyoxylate is converted oxalate using lactate dehydrogenase. Unused ascorbic acid can be also used to synthesize oxalate in the body. Although the specific reactions and enzymes involved are still unknown, there is a general sense of what metabolites are formed during oxalate synthesis from ascorbic acid. Ascorbic acid forms dehydroascorbic acid, which then forms 2,3-diketo-L-gulonate. 2,3-diketo-L-gulonate can be converted to oxalate. The oxalate formed in the liver form these 3 sources can enter the blood and have toxic effects in other tissues. Oxalate can promote cardiovascular disease, neurotoxicity and inflammation.

p-Cresol sulfate is a microbial metabolite that is found in urine and likely derives from secondary metabolism of p-cresol. It appears to be elevated in the urine of individuals with progressive multiple sclerosis. p-Cresol sulfate is the major component of urinary MBPLM (myelin basic protein-like material). p-Cresol sulfate is a small protein-bound molecule that is poorly cleared with dialysis. It has been identified as a uremic toxin according to the European Uremic Toxin Working Group. Uremic toxins include other low-molecular-weight compounds such as indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, and asymmetric dimethylarginine. It has also been linked to cardiovascular disease and oxidative injury. Higher levels are associated with overgrowth of intestinal bacteria from Clostridia species, including C. difficile. p-Cresol is generated by the partial breakdown of tyrosine and phenylalanine by a wide range of intestinal obligate or facultative anaerobes, including the genera Bacteroides, Lactobacillus, Enterobacter, Bifidobacterium, and especially Clostridium. The reversible reaction of l-tyrosine with 2-oxoglutarate in 4-hydroxyphenylpyruvate and L-glutamate is catalysed by tyrosine transaminase (EC 2.6.1.5.) or by aromatic-amino-acid transaminase (EC 2.6.1.57.) To a small extent, 4-hydroxyphenylpyruvate and ammonia can also be formed by the enzyme phenylalanine dehydrogenase (EC 1.4.1.20.) from l-tyrosine. 4-Hydroxyphenylpyruvate is the precursor of 4-hydroxyphenylacetate, catalysed by p-hydroxyphenylpyruvate oxidase (EC 1.2.3.13.), and can subsequently lead to the formation of p-cresol by p-hydroxyphenylacetate decarboxylase. In the gut mucosa and in the liver, the majority of p-cresol will be conjugated into the uremic toxin p-cresyl sulfate by aryl sulfotransferases (EC 2.8.2.1.).

Para-Hydroxyphenylacetic acid, also known as 4-hydroxybenzeneacetate, is classified as a member of the 1-hydroxy-2-unsubstituted benzenoids. 1-Hydroxy-2-unsubstituted benzenoids are phenols that are unsubstituted at the 2-position. p-Hydroxyphenylacetic acid is considered to be slightly soluble (in water) and acidic. p-Hydroxyphenylacetic acid can be synthesized from acetic acid. It is also a parent compound for other transformation products, including but not limited to, methyl 2-(4-hydroxyphenyl)acetate, ixerochinolide, and lactucopicrin 15-oxalate. p-Hydroxyphenylacetic acid can be found in numerous foods such as olives, cocoa beans, oats, and mushrooms. p-Hydroxyphenylacetic acid can be found throughout all human tissues and in all biofluids. Within a cell, p-hydroxyphenylacetic acid is primarily located in the cytoplasm and in the extracellular space. p-Hydroxyphenylacetic acid is also a microbial metabolite produced by Acinetobacter, Clostridium, Klebsiella, Pseudomonas, and Proteus. Higher levels of this metabolite are associated with an overgrowth of small intestinal bacteria from Clostridia species including C. difficile, C. stricklandii, C. lituseburense, C. subterminale, C. putrefaciens, and C. propionicum .The reversible reaction of l-tyrosine with 2-oxoglutarate in 4-hydroxyphenylpyruvate and L-glutamate is catalysed by tyrosine transaminase (EC 2.6.1.5.) or by aromatic-amino-acid transaminase (EC 2.6.1.57.) To a small extent, 4-hydroxyphenylpyruvate and ammonia can also be formed by the enzyme phenylalanine dehydrogenase (EC 1.4.1.20.) from l-tyrosine. 4-Hydroxyphenylpyruvate is the precursor of 4-hydroxyphenylacetate, catalysed by p-hydroxyphenylpyruvate oxidase (EC 1.2.3.13.).

Para-cresol(P-cresol) is a phenolic compound that is formed through gut microbial metabolism from the amino acid tyrosine which is acquired from foods that are high in protein. After being transported into gut microbes, tyrosine undergoes reactions with the enzymes tyrosine transaminase, 4-hydroxyphenylpyruvate oxidase and 4-hydroxylphenylacetate decarboxylase to form para-cresol. Most of the p-cresol that is produced from the gut microbes then enters systemic circulation. P-cresol can then undergo sulfation or glucuronidation reactions in the liver to produce the uremic toxins p-cresyl sulfate and p-cresyl glucuronide respectively. However, P-cresol itself can also be a uremic toxin with widespread toxic effects on the body. P-cresol is shown to be associated with cardiovascular disease and it can also inhibit endothelial cell proliferation.

Para-cresyl glucuronide (P-cresyl 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 reactions with the enzymes tyrosine transaminase, 4-hydroxyphenylpyruvate oxidase and 4-hydroxylphenylacetate decarboxylase to form para-cresol. Most of the p-cresol that is produced from the gut microbes then enters systemic circulation and is converted into P-cresyl sulphate by the liver. However a small portion also gets converted to P-cresyl glucuronide. This occurs when P-cresol then undergoes a reaction in a liver hepatocyte through a glucuronosyltransferase enzyme to form P-cresyl glucuronide. When P-cresyl glucuronide returns back into systemic circulation it is shown to be a uremic toxin with some similar effects to P-cresyl sulphate. P-cresyl glucuronide is shown to induce stress in renal tubule cells as well as the effect shared by p-cresyl sulphate in causing enhanced oxidative stress.

Para-cresyl sulphate(P-cresyl 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 reactions with the enzymes tyrosine transaminase, 4-hydroxyphenylpyruvate oxidase and 4-hydroxylphenylacetate decarboxylase to form para-cresol. Most of the p-cresol that is produced from the gut microbes then enters systemic circulation. P-cresol then ultimately undergoes a sulfation reaction in a liver hepatocyte through a sulfotransferase enzyme to form P-cresyl sulphate. When P-cresyl sulphate returns back into systemic circulation it is shown to be a major uremic toxin through high levels of retention. P-cresyl sulphate is shown to cause carotid atherosclerosis and enhance reactive oxygen species production causing cardiac toxicity and leads to cardiomyocyte apoptosis.

Phenol is a phenolic compound that is formed through gut microbial metabolism from dietary tyrosine. 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. Phenol can get further metabolized in a liver hepatocyte to Phenyl sulphate and Phenyl glucuronide. However phenol itself is shown to be a major uremic toxin through high levels of retention. Phenol is shown to cause cardiovascular disease and enhance the production of reactive oxygen species and cause oxidative stress.

Phenol sulphate, also known as phenylsulfate or aryl sulphate, belongs to the class of organic compounds known as phenylsulfates. Phenylsulfates are compounds containing a sulfate group conjugated to a phenyl group. In normal humans, phenol sulphate is primarily a gut-derived metabolite that arises from the activity of the bacterial enzyme tyrosine phenol-lyase, which is responsible for the synthesis of phenol from dietary tyrosine. Phenol sulphate can also arise from the consumption of phenol or from phenol poisoning. Phenol sulphate is produced from the conjugation of phenol with sulphate in the liver. In particular, phenol sulphate can be biosynthesized from phenol and phosphoadenosine phosphosulfate through the action of the enzyme sulfotransferase 1A1 in the liver. Phenol sulphate can be found in most mammals (mice, rats, sheep, dogs, humans) and likely most animals. Phenol sulphate is a uremic toxin. It is a protein-bound uremic solute that induces reactive oxygen species (ROS) production and decreases glutathione levels, rendering cells vulnerable to oxidative stress. In experimental models of diabetes, phenol sulphate administration has been shown to induce albuminuria and podocyte damage. In a diabetic patient cohort, phenol sulphate levels were found to significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Tyrosine is converted to phenol by a bacterial enzyme called tyrosine phenol-lyase before it is converted to phenol sulphate in the liver by sulfotransferase 1A1.