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IUPAC name
5-amino-5-oxo-2-[(1-oxo-2-phenylethyl)amino]pentanoic acid
3D model (JSmol)
Molar mass 264.281 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Phenylacetylglutamine is a product formed by the conjugation of phenylacetate and glutamine. It is a common metabolite that is naturally occurring in human urine.

The highly-nitrogenous compound most commonly encountered in the human subjects with urea cycle disorders, associated with uremic conditions in the body. 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.[1]


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, glycerol phenylbutyrate, and sodium phenylacetate, considered more toxic, that are used as treatments for the physiological dysfunction in urea cycling.[2]

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.[3]

The metabolism and conjugation of phenylacetate with glutamine in the liver involves amino acid acetylation carried out by the enzyme 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.[4][5] 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[edit]

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.[6] 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.[7][8] 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.[4]

Chronic kidney disorder[edit]

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 (CKD).[9] In CKD phenylacetylglutamine is considered a uremic toxin, which is uptaken, circulated and retained in the blood after microbial fermentation of certain proteins and amino acids in the gut.[10] 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 heart failure, cardiovascular risk, or hypertension, in the development of renal disease and in patients with type 2 diabetes.[9]

See also[edit]


  1. ^ Jiang Y, Almannai M, Sutton VR, Sun Q, Elsea SH (November 2017). "Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels". Molecular Genetics and Metabolism. 122 (3): 39–45. doi:10.1016/j.ymgme.2017.08.011. PMID 28888854.
  2. ^ Palir N, Ruiter JP, Wanders RJ, Houtkooper RH (May 2017). "Identification of enzymes involved in oxidation of phenylbutyrate". Journal of Lipid Research. 58 (5): 955–961. doi:10.1194/jlr.M075317. PMC 5408614. PMID 28283530.
  3. ^ Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Bartley J, Feigenbaum A, et al. (November 2012). "Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders". Molecular Genetics and Metabolism. 107 (3): 308–14. doi:10.1016/j.ymgme.2012.08.006. PMC 3608516. PMID 22958974.
  4. ^ a b Yang D, Brunengraber H (April 2000). "Glutamate, a window on liver intermediary metabolism". The Journal of Nutrition. 130 (4S Suppl): 991S–4S. doi:10.1093/jn/130.4.991s. PMID 10736368.
  5. ^ Moldave K, Meister A (August 1957). "Participation: of phenylacetyl-adenylate in the enzymic synthesis of phenylacetylglutamine". Biochimica et Biophysica Acta. 25 (2): 434–5. doi:10.1016/0006-3002(57)90500-0. PMID 13471596.
  6. ^ Machado MC, Pinheiro da Silva F (2014-03-13). "Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting". Journal of Intensive Care. 2 (1): 22. doi:10.1186/2052-0492-2-22. PMC 4407289. PMID 25908985.
  7. ^ Brusilow SW (February 1991). "Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion". Pediatric Research. 29 (2): 147–50. doi:10.1203/00006450-199102000-00009. PMID 2014149.
  8. ^ Mokhtarani M, Diaz GA, Lichter-Konecki U, Berry SA, Bartley J, McCandless SE, et al. (December 2015). "Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate". Molecular Genetics and Metabolism Reports. 5: 12–14. doi:10.1016/j.ymgmr.2015.09.003. PMC 5471406. PMID 28649536.
  9. ^ a b Barrios C, Beaumont M, Pallister T, Villar J, Goodrich JK, Clark A, et al. (August 2015). "Gut-Microbiota-Metabolite Axis in Early Renal Function Decline". PLOS One. 10 (8): e0134311. doi:10.1371/journal.pone.0134311. PMC 4524635. PMID 26241311.
  10. ^ Hung SC, Kuo KL, Wu CC, Tarng DC (February 2017). "Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease". Journal of the American Heart Association. 6 (2): e005022. doi:10.1161/jaha.116.005022. PMC 5523780. PMID 28174171.