Amino Acids

, Volume 47, Issue 9, pp 1893–1908 | Cite as

Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free l-arginine in humans

  • Arslan Arinc Kayacelebi
  • Jennifer Langen
  • Katharina Weigt-Usinger
  • Kristine Chobanyan-Jürgens
  • François Mariotti
  • Jessica Y. Schneider
  • Sabine Rothmann
  • Jürgen C. Frölich
  • Dorothee Atzler
  • Chi-un Choe
  • Edzard Schwedhelm
  • Jean François Huneau
  • Thomas Lücke
  • Dimitrios TsikasEmail author
Original Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives


Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas l-arginine (Arg) and l-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N G)-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S-adenosylmethionine (SAM) as the methyl donor. l-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N G-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N G-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive.


ADMA Arginine Homoarginine Knockout mouse NG-Methyltransferases SAM 



Asymmetric dimethylarginine (l-N G,N G-dimethylarginine)


Arginine:glycine amidinotransferase


Coronary artery disease




Dimethylarginine dimethylaminohydrolase






Guanidinoacetate methyltransferase


Gas chromatography–mass spectrometry


Gas chromatography–tandem mass spectrometry


Growth hormone deficiency








l-N G-Monomethylarginine


Nitric oxide


Nitric oxide synthase


Peripheral arterial occlusive disease


Protein arginine methyltransferase




Symmetric dimethylarginine (l-N G, G-dimethylarginine)


Wild type


Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All studies reported here were approved by the local Ethics Committees for animals and humans. All adult participants and the parents of the children gave their written informed consent prior to enrolment.


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Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Arslan Arinc Kayacelebi
    • 1
  • Jennifer Langen
    • 2
  • Katharina Weigt-Usinger
    • 2
  • Kristine Chobanyan-Jürgens
    • 1
  • François Mariotti
    • 3
    • 4
  • Jessica Y. Schneider
    • 1
  • Sabine Rothmann
    • 1
  • Jürgen C. Frölich
    • 1
  • Dorothee Atzler
    • 5
    • 6
  • Chi-un Choe
    • 7
    • 8
  • Edzard Schwedhelm
    • 5
    • 6
  • Jean François Huneau
    • 3
    • 4
  • Thomas Lücke
    • 2
  • Dimitrios Tsikas
    • 1
    Email author
  1. 1.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  2. 2.Department of Neuropaediatrics, University Children’s HospitalRuhr UniversityBochumGermany
  3. 3.INRACRNH-IdF, UMR914 Nutrition Physiology and Ingestive BehaviorParisFrance
  4. 4.AgroParisTechCRNH-IdF, UMR914 Nutrition Physiology and Ingestive BehaviorParisFrance
  5. 5.Department of Clinical Pharmacology and ToxicologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.DZHK (German Centre for Cardiovascular Research)HamburgGermany
  7. 7.Department of NeurologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  8. 8.Experimental NeuropediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany

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