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Arginine:glycine amidinotransferase

Arginine:glycine amidinotransferase
Protein Structure/Function
Molecular Weight: 91800 (Homo sapien wild-type enzyme) (Da)
Functions: Catalyses the transfer of an amidino group from L-arginine to glycine, committed step in creatine synthesis
Cell types:Pancreas, kidneys and liver.
Subcellular localization:Cytoplasm and intermembrane space of the mitochondria.
Pathway(s):Creatine metabolism
Enzymatic Data
Catalytic activity:L-arginine + glycine = L-ornithine + guanidinoacetate
Enzyme Regulation:Repressed by orthinine, creatine (the end-product of the pathway), cyclocreatine, N-acetimidoylsarcosine, and N-ethylguanidinoacetate. Regulated by growth hormones and thyroxine
Medical/Biotechnological data
Diseases:AGAT deficiency which is a genetic defect expressed as mental retardation
Database Links
EC number:



L-Arginine:glycine amidinotransferase (AGAT; EC is the enzyme that catalyses the transfer of an amidino group from L-arginine to glycine. The result of this is L-ornithine and guanidinoacetate, which is the immediate precursor of creatine. Creatine and its phosphorylated form play a central role in the energy metabolism of muscle and nerve tissues. L-Arginine:glycine amidinotransferase catalyses the first, which is also the committed, step in the formation of creatine. Creatine is in highest concentrations in the skeletal muscle, heart, spermatozoa and photoreceptor cells. Creatine helps buffer the rapid changes in ADP/ATP ratio in muscle and nerve cells during active periods. However, creatine is synthesized in other tissue such as pancreas, kidneys and liver where amidinotransferase is located in the cytoplasm and intermembrane space of the mitochondria of the cells that make those tissues. [1] The second step of the process, where creatine is actually a product, occurs solely in the cytosol, as this is where the second enzyme, S-adenosylmethionine:guanidinoacetate methyltransferase (GMT) is only found. The creatine is then transported through the bloodstream and taken up by the necessary cells through sodium-dependent creatine transporters. [2]


The crystal structure of AGAT was determined by Humm, Fritsche, Steinbacher, and Huber of the Max Planck Institute for Biochemistry in Martinsried, Germany in 1997. X-ray examinations of the structure reveal a novel symmetry with five-fold pseudosymmetry of beta beta alphabeta modules. The overall structure of the molecule resembles a basket with handles. The active site lies at the bottom of a long, narrow channel and includes a Cys-His-Asp catalytic triad. The intermediate structure involves the amidino group temporarily covalently bonding to the Cys residue on the catalytic triad, while the His residue takes part in general acid/base catalysis, meaning it acts as a proton donator/receiver itself.[1]




The actual reaction catalyzed by AGAT is the synthesis of guanidinoacetate from arginine and glycine, with ornithine as a byproduct. The guanidinoacetate produced is then combined with S-Ado-Methionine, a reaction catalyzed by GMT, to produce creatine and S-Ado-Homocysteine. The mechanism by which the AGAT catalyzes this committed step follows a ping-pong mechanism, and involves the transferring of an amidino group to the Cys407 residue on the protein from L-arginine, which leaves as L-ornithine. The His303 residue then extracts a proton from glycine, which then picks up the amidino group from Cys407 in exchange for a proton to become guanidinoacetate and renew the catalyst. [1]

Regulation of AGAT Expression and Activity

The formation of guanidinoacetate is normally the rate-limiting step of creatine biosynthesis. [3] Consequently, the AGAT reaction is the most likely control step in the pathway, a hypothesis that is supported by a great deal of experimental work. Most important in this respect is the feedback repression of AGAT by creatine, the end-product of the pathway. Cyclocreatine, N-acetimidoylsarcosine, and N-ethylguanidinoacetate display repressor activity like creatine as well. L-Arginine and guanidinoacetate have only "apparent" repressor activity. They exert no effect on AGAT expression by themselves but are readily converted to creatine, which then acts as the true repressor. [4] It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone and thyroxine,[5] inhibition of the enzyme by ornithine, [6] and repression of its synthesis by creatine [7] [8]

AGAT Deficiency

In 2000, The American Journal of Human Genetics reported two female siblings, aged 4 and 6 years, with mental retardation and severe creatine deficiency in the brain. [9] Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. Patients with brain creatine deficiency present nonspecific neurologic symptoms, including mental retardation, language disorders, epilepsy, autistic-like behavior, neurologic deterioration, and movement disorders. A deficiency in AGAT results in a creatine deficiency in the body. The treatment for this is creatine supplements since the body cannot make the creatine on its own. The positive results of creatine treatment (in AGAT deficiencies) and the observation that fetal and early postnatal development are normal in these patients support the hypothesis that earlier diagnosis and treatment can substantially improve the final prognosis of these diseases. Brain 1H-MRS examination is a reliable and minimally invasive technique to assess brain creatine disorders. Because of its limited availability and high cost, the 1H-MRS technique cannot be proposed for all children whose clinical condition suggests the diagnosis of brain creatine depletion. [10] AGAT deficiency is, along with GMT deficiency and creatine transporter defect, one of three inborn errors of the creatine biosynthesis/transport pathway. The prevalence of these defects is unknown, however they have been observed to occur in high frequency in mentally retarded children. The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149. [11]

AGAT and Heart Failure

During the end-stage of heart failure, microarray analysis revealed a significant and unexpected decrease in myocardial arginine:glycine amidinotransferase (AGAT) gene expression. This suggests that the reduced AGAT correlates with loss of heart function. Increase of AGAT expression in the myocardium after heart failure responded in favorable results due to increase in creatine synthesis. These findings have implications both for the management of recovery patients undergoing combination therapy and for heart failure in general. [12]

AGAT and Sex Hormones

Sex hormones can regulate the activity of AGAT. [13] Treatment of male rats with testosterone propionate increases AGAT activity. In contrast, estrogen treatment decreases AGAT activity and induces weight loss. So, this is the first report showing that estrogen can regulate the expression of AGAT transcript. However, it is currently unclear whether the changes in the level of AGAT transcript results from altered mRNA stability or enhanced transcriptional rate. If estrogen-mediated alteration results from transcriptional regulation, the site of estrogen action is yet to be determined. [14]


  1. ^ a b c A Humm, E Fritsche, K Mann, M Göhl, and R Huber; "Recombinant expression and isolation of human L-arginine:glycine amidinotransferase and identification of its active-site cysteine residue"; Biochem J. 1997 March 15; 322(Pt 3): 771–776
  2. ^ a b c d Andreas Humm, Erich Fritsche, Stefan Steinbacher and Robert Huber; Crystal structure and mechanism of human L-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis; The EMBO Journal (1997) 16, 3373–3385, doi:10.1093/emboj/16.12.3373
  3. ^ WALKER JB Creatine: biosynthesis, regulation, and function. Adv Enzymol 50: 177-242, 1979
  4. ^ Markus Wyss and Rima Kaddurah-Daouk ; Creatine and Creatinine Metabolism; Physiological Reviews, Vol. 80, No. 3, July 2000, pp. 1107-1213
  5. ^ McGuire, D. M., Tormanen, C. D., Segal, I. S. and Van Pilsum, J. F. (1980) J. Biol.Chem. 255, 1152-1159
  6. ^ Sipila, I. (1980) Biochim. Biophys. Acta 613, 79-84
  7. ^ McGuire, D. M., Gross, M. D., Van Pilsum, J. F. and Towle, H. C. (1984) J. Biol.Chem. 259, 12034-12038
  8. ^ Guthmiller, P., Van Pilsum, J. F., Boen, J. R. and McGuire, D. (1994) J. Biol. Chem. 269, 17556-17560
  9. ^ Chike Bellarmine Item,Sylvia Stöckler-Ipsiroglu, Carmen Stromberger, Adolf Mühl, Maria Grazia Alessandrì, Maria Cristina Bianchi, Michela Tosetti, Francesco Fornai, and Giovanni Cioni; Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans; Am J Hum Genet. 2001 November; 69(5): 1127–1133.
  10. ^ Claudia Carducci, Maurizio Birarelli, Vincenzo Leuzzi, Carla Carducci, Roberta Battini, Giovanni Cioni and Italo Antonozzi; Guanidinoacetate and Creatine plus Creatinine Assessment in Physiologic Fluids: An Effective Diagnostic Tool for the Biochemical Diagnosis of Arginine:Glycine Amidinotransferase and Guanidinoacetate Methyltransferase Deficiencies ; Clinical Chemistry. 2002;48:1772-1778
  11. ^ Item CB, Stockler-Ipsiroglu S, Stromberger C, Muhl A. “Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans.” Am J Hum Genet. 69 (2001): 1127-33
  12. ^ Cullen ME, Yuen AH, Felkin LE; Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis; Circulation. 2006 Jul 4;114(1 Suppl):I16-20
  13. ^ Krisko I, Walker JB: Influence of sex hormones on amidinotransferase levels. Metabolic control of creatine biosynthesis. Acta Endocrinol (Copenh) 53: 655–662, 1966
  14. ^ Zhu Y, Evans MI; Estrogen modulates the expression of L-arginine:glycine amidinotransferase in chick liver; Mol Cell Biochem. 2001 May;221(1-2):139-45
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Arginine:glycine_amidinotransferase". A list of authors is available in Wikipedia.
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