Phenylacetylglutamine is a product formed by the

conjugation Conjugation or conjugate may refer to: Linguistics * Grammatical conjugation, the modification of a verb from its basic form * Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics * Complex conjugation, the chang ...

of phenylacetate and

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...

. It is a common

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

that occurs naturally in human

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

. The highly-nitrogenous compound is most commonly encountered in human subjects with

urea cycle disorder Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

s,. These conditions, such as

uremia Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess of amino acid and protein metabolism end products, such as urea and creatinine, in the blood that would be no ...

hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. It i ...

, 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.

Metabolism

Phenylacetylglutamine is the primary metabolite of the degradation of phenylacetate when in the presence of glutamine in the liver. It is also produced in higher concentrations in the body through the metabolic degradation pathway of the pharmaceutical compounds

sodium phenylbutyrate Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an ...

glycerol phenylbutyrate Glycerol phenylbutyrate (USAN), trade name Ravicti, is a medication used in the treatment of certain inborn urea cycle disorders. The medication works by preventing the harmful buildup of ammonia in the body. It is an FDA-approved prescription dr ...

, and sodium phenylacetate, considered more toxic, that are used as treatments for the physiological dysfunction in urea cycling. Phenylbutyrate is beta-oxidized into phenylacetate which is conjugated with glutamine in the liver and excreted by the kidney. Phenylacetylglutamine is the product of uremic conditions that require an alternative pathway to the urea cycle for nitrogen waste removal. This process produces comparable levels of phenylacetylglutamine in urine in relation to urea levels in a properly functioning urea cycle. In 24 hours 80-100% of a dose of phenylbutyrate is excreted in the urine as phenylacetylglutamine. The metabolism and conjugation of phenylacetate with glutamine in the liver involves amino acid acetylation carried out by the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

phenylacetyltranferase or glutamine N-acetyl transferase. The enzyme catalyzes the reaction of the substrates phenylacetyl-CoA and L-glutamine to produce CoA and alpha-N-phenylacetyl-L-glutamine and phenylacetic acid. The catalytic enzyme has been isolated in the human liver mitochondria. Furthermore, phenylacetylglutamine has been found in human urine, but not in the excretory material of rats, dogs, cats, monkeys, sheep, or horses. Throughout the metabolic process, phenylacetylglutamine is bound and conjugated by free-plasma in the kidney to remove excess nitrogen through its excretion in the urine.

As a biomarker

Elevated levels of nitrogen in the blood increase the amount of glutamine, the primary, non-toxic carrier of ammonia in the blood, within patients with hyperammonemia and inborn errors in urea synthesis. Phenylacetylglutamine levels in the urine serves as a more effective biomarker for the excretion of nitrogenous waste than measures of blood plasma, which fluctuate and are a less effective therapeutic monitor of waste nitrogen levels. A 24-hour metabolic urine test of phenylacetylglutamine provides a non-invasive biomarker of waste nitrogen that most consistently reflects the dose of phenylbutyric acid or glycerol phenylbutyrate used to treat patients with urea-cycle disorders. Phenylacetylglutamine isotopically labeled with ¹⁴C also serves more broadly to characterize relative rates of cellular reactions and functions as a general, non-invasive biomarker for gluconeogenesis and citric acid cycle intermediates in the liver.

Chronic kidney disorder

High levels of phenylacetylglutamine in the urine following metabolism by the gut microbiota may also indicate early renal decline associated with kidney dysfunction and

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

(CKD). In CKD, phenylacetylglutamine is considered a uremic toxin which is taken up, circulated and retained in the blood after microbial fermentation of certain proteins and amino acids in the gut. Blood serum levels of phenylacetylglutamine in CKD are used as a mortality determinant. Blood plasma levels of phenylacetylglutamine increase with exposure to cigarette smoke, in patients with

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...

heart failure, with cardiovascular risk or hypertension, in the development of renal disease, and in patients with type 2 diabetes.

References

{{Reflist, 32em Carboxamides Phenyl compounds

Metabolism

As a biomarker

Chronic kidney disorder

See also

References