p-Cresyl Sulfate

Tessa Gryp, Raymond Vanholder, Mario Vaneechoutte, Griet Glorieux, Tessa Gryp, Raymond Vanholder, Mario Vaneechoutte, Griet Glorieux

Abstract

If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.

Keywords: chronic kidney disease; intestinal microbiota; p-cresyl sulfate.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Conversion pathway of tyrosine and phenylalanine into p-cresyl sulfate. Full arrows: process through bacterial fermentation; dotted arrows: process through enzymatic reactions of the host; EC: enzyme commission number. l-tyrosine, derived from diet and endogenous proteins and peptides, can be converted to phenol and 4-hydroxyphenylpyruvate. Tyrosine phenol-lyase (EC 4.1.99.2.), previously named β–tyrosinase, is responsible for the reversible deamination of l-tyrosine, requiring pyridoxyl phosphate as a cofactor, into phenol ammonia and pyruvate [40,41,42]. This reaction is also reversible by the same enzyme using l-serine and phenol as substrates [43]. In addition, 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.) [44,45,46]. 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 [47]. 4-Hydroxyphenylpyruvate is the precursor of 4-hydroxyphenylacetate, catalysed by p-hydroxyphenylpyruvate oxidase (EC 1.2.3.13.) [44,46], and can subsequently lead to the formation of p-cresol by p-hydroxyphenylacetate decarboxylase (EC 4.1.1.83.) [48,49]. 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.) [50] and a small fraction will be metabolized to p-cresyl glucuronide by UDP-glucuronyltransferases (EC 2.4.1.17.) [51]. Another aromatic amino acid, phenylalanine, also plays a role in the production of p-cresyl sulfate through the hydroxylation reaction to tyrosine by phenylalanine 4-monooxygenase, also referred as phenylalanine hydroxylase (EC 1.14.16.1.) [52]. This metabolic process is carried out by bacteria as well by liver cells, transforming excess diet phenylalanine to tyrosine [53]. In addition, phenylalanine is converted into 3-phenylpyruvate by either phenylalanine dehydrogenase (EC 1.4.1.20.) [47,54], branched-chain-amino-acid transaminase (EC 2.6.1.42.) [55] or by aromatic-amino-acid transaminase (EC 2.6.1.57.) [45]. Then 3-phenylpyruvate can be transformed in 3-phenylacetaldehyde by phenylpyruvate decarboxylase (EC 4.1.1.43.) [56] or in 3-phenyllactate by l-lactate dehydrogenase (EC 1.1.1.27.) [46]. Finally, 3-phenylacetaldehyde can be converted to 3-phenylacetate by phenylacetaldehyde dehydrogenase (EC 1.2.1.39.) [56,57]. All of these reactions of the phenylalanine metabolic pathway are reversible, which can lead, in the end, to p-cresyl sulfate generation.

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