Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ADMA:

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

AGAT:

Arginine:glycine amidinotransferase

CAD:

Coronary artery disease

Cr:

Creatine

DDAH:

Dimethylarginine dimethylaminohydrolase

DMA:

Dimethylamine

GAA:

Guanidinoacetate

GAMT:

Guanidinoacetate methyltransferase

GC–MS:

Gas chromatography–mass spectrometry

GC–MS/MS:

Gas chromatography–tandem mass spectrometry

GHD:

Growth hormone deficiency

hArg:

Homoarginine

KO:

Knockout

Me:

Methyl

MMA:

l-N G-Monomethylarginine

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PAOD:

Peripheral arterial occlusive disease

PRMT:

Protein arginine methyltransferase

SAM:

S-Adenosylmethionine

SDMA:

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

WT:

Wild type

References

  • Atzler D, Rosenberg M, Andersso M, Choe CU, Lutz M, Zugck C et al (2013) Homoarginine—an independent marker of mortality in heart failure. Int J Cardiol 168:4907–4909

    Article  PubMed  Google Scholar 

  • Atzler D, Gore MO, Ayers CR, Choe CU, Böger RH, de Lemos JA, McGuire DK, Schwedhelm E (2014) Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler Thromb Vasc Biol 34:2501–2507

    Article  CAS  PubMed  Google Scholar 

  • Bode-Böger SM (2006) Effect of arginine supplementation on NO production in man. Eur J Clin Pharmacol 62:91–99

    Article  Google Scholar 

  • Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC (1998) Arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 46:489–497

    Article  PubMed Central  PubMed  Google Scholar 

  • Bode-Böger SM, Böger RH, Löffler M, Tsikas D, Brabant G, Frölich JC (1999) l-Arginine stimulates NO-dependent vasodilation in healthy humans—effect of somatostatin pretreatment. J Investig Med 47:43–50

    PubMed  Google Scholar 

  • Böger RH, Maas R, Schulze F, Schwedhelm E (2009) Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality-an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 60:481–487

    Article  PubMed  Google Scholar 

  • Bretscher LE, Li H, Poulos TL, Griffith OW (2003) Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines. J Biol Chem 278:46789–46797

    Article  CAS  PubMed  Google Scholar 

  • Brosnan ME, Brosnan JT (2004) Renal arginine metabolism. J Nutr 134:2791S–2895S

    CAS  PubMed  Google Scholar 

  • Burnett GH, Cohen PP (1957) Study of carbamyl phosphate-ornithine transcarbamylase. J Biol Chem 229:337–344

    CAS  PubMed  Google Scholar 

  • Cathelineau L, Saudubray JM, Charpentier C, Polonovski C (1974) Letter: the presence of the homoanalogues of substrates of the urea cycle in the presence of argininosuccinate synthetase deficiency. Pediatr Res 8:857

    Article  CAS  PubMed  Google Scholar 

  • Choe CU, Atzler D, Wild PS, Carter AM, Boger RH, Ojeda F et al (2013a) Homoarginine levels are regulated by arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461

    Article  CAS  PubMed  Google Scholar 

  • Choe CU, Nabuurs C, Stockebrand MC, Neu A, Nunes P, Morellini F et al (2013b) Arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum Mol Genet 22:110–123

    Article  CAS  PubMed  Google Scholar 

  • Cullen ME, Yuen AH, Felkin LE, Smolenski RT, Hall JL, Grindle S et al (2006) Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation 114:I16–I20

    Article  PubMed  Google Scholar 

  • da Silva RP, Clow K, Brosnan JT, Brosnan ME (2014) Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br J Nutr 111:571–577

    Article  PubMed  Google Scholar 

  • Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T (2012a) Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett 586:3653–3657

    Article  CAS  PubMed  Google Scholar 

  • Davids M, Swieringa E, Palm F, Smith DE, Smulders YM, Scheffer PG et al (2012b) Simultaneous determination of asymmetric and symmetric dimethylarginine, l-monomethylarginine, arginine, and l-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry. J Chromatogr B 900:38–47

    Article  CAS  Google Scholar 

  • Drechsler C, Meinitzer A, Pilz S, Krane V, Tomaschitz A, Ritz E et al (2011) Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients. Eur J Heart Fail 13:852–859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hecker M, Walsh DT, Vane JR (1991) On the substrate specificity of nitric oxide synthase. FEBS Lett 294:221–224

    Article  CAS  PubMed  Google Scholar 

  • Horner WH, Mackenzie CG (1950) The biological formation of sarcosine. J Biol Chem 187:15–22

    CAS  PubMed  Google Scholar 

  • Humm A, Fritsche E, Steinbacher S, Huber R (1997) Crystal structure and mechanism of human l-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. EMBO J 16:3373–3385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jaźwińska-Kozuba A, Martens-Lobenhoffer J, Kruszelnicka O, Rycaj J, Chyrchel B, Surdacki A, Bode-Böger SM (2013) Opposite associations of plasma homoarginine and ornithine with arginine in healthy children and adolescents. Int J Mol Sci 14:21819–21832

    Article  PubMed  Google Scholar 

  • Kato T, Sano M, Mizutani N, Hayakawa C (1988) Homocitrullinuria and homoargininuria in hyperargininaemia. J Inherit Metab Dis 11:261–265

    Article  CAS  PubMed  Google Scholar 

  • Katz JE, Dlakić M, Clarke S (2003) Automated identification of putative methyltransferases from genomic open reading frames. Mol Cell Proteomics 2:525–540

    CAS  PubMed  Google Scholar 

  • Kayacelebi AA, Nguyen TH, Neil C, Horowitz JD, Jordan J, Tsikas D (2014a) Homoarginine and 3-nitrotyrosine in patients with takotsubo cardiomyopathy. Int J Cardiol 173:546–547

    Article  PubMed  Google Scholar 

  • Kayacelebi AA, Beckmann B, Gutzki FM, Jordan J, Tsikas D (2014b) GC–MS and GC–MS/MS measurement of the cardiovascular risk factor homoarginine in biological samples. Amino Acids 46:2205–2217

    Article  CAS  PubMed  Google Scholar 

  • Kayacelebi AA, Knöfel AK, Beckmann B, Hanff E, Warnecke G, Tsikas D (2015a) Measurement of unlabeled and stable isotope-labeled homoarginine, arginine and their metabolites in biological samples by GC–MS and GC–MS/MS. Amino Acids. doi:10.1007/s00726-015-1984-3

    Google Scholar 

  • Kayacelebi AA, Willers J, Pham VV, Hahn A, Schneider JY, Rothmann S, Frölich JC, Tsikas D (2015b) Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease. Amino Acids. doi:10.1007/s00726-015-1915-3

    Google Scholar 

  • Khalil AA, Tsikas D, Akolekar R, Jordan J, Nicolaides KH (2013) Asymmetric dimethylarginine, arginine and homoarginine at 11–13 weeks’ gestation and preeclampsia: a case-control study. J Hum Hypertens 27:38–43

    Article  CAS  PubMed  Google Scholar 

  • Kielstein A, Tsikas D, Galloway GP, Mendelson JE (2007) Asymmetric dimethylarginine (ADMA)—a modulator of nociception in opiate tolerance and addiction? Nitric Oxide 17:55–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leiper J, Vallance P (1999) Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43:542–548

    Article  CAS  PubMed  Google Scholar 

  • Levin B, Oberholzer VG, Palmer T (1974) Letter: the high levels of lysine, homocitrulline, and homoarginine found in argininosuccinate synthetase deficiency. Pediatr Res 8:857–858

    Article  CAS  PubMed  Google Scholar 

  • Lücke T, Tsikas D, Kanzelmeyer N, Vaske B, Das AM (2006) Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine in citrullinemia. Metabolism 55:1599–1603

    Article  PubMed  Google Scholar 

  • MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H et al (1996) Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mariotti F, Petzke KJ, Bonnet D, Szezepanski I, Bos C, Huneau JF et al (2013) Kinetics of the utilization of dietary arginine for nitric oxide and urea synthesis: insight into the arginine-nitric oxide metabolic system in humans. Am J Clin Nutr 97:972–979

    Article  CAS  PubMed  Google Scholar 

  • Martens-Lobenhoffer J, Bode-Böger SM (2012) Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: a step improvement in precision by stable isotope dilution mass spectrometry. J Chromatogr B 904:140–143

    Article  CAS  Google Scholar 

  • März W, Meinitzer A, Drechsler C, Pilz S, Krane V, Kleber ME et al (2010) Homoarginine, cardiovascular risk, and mortality. Circulation 122:967–975

    Article  PubMed  Google Scholar 

  • McGuire DM, Tormanen CD, Segal IS, Van Pilsum JF (1980) The effect of growth hormone and thyroxine on the amount of l-arginine:glycine amidinotransferase in kidneys of hypophysectomized rats. Purification and some properties of rat kidney transamidinase. J Biol Chem 255:1152–1159

    CAS  PubMed  Google Scholar 

  • Miller LL, Bale WF, Yuile CL, Masters RE, Tishkoff GH, Whipple GH (1949) The use of radioactive lysine in studies on protein metabolism. Synthesis and utilization of plasma proteins. J Exp Med 90:297–313

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D (1998) Substrate specificity of NO synthases: detailed comparison of arginine, homo-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-arginine. Biochemistry 37:10453–10460

    Article  CAS  PubMed  Google Scholar 

  • Moncada S, Higgs A (1993) The arginine-nitric oxide pathway. New Engl J Med 329:2002–2012

    Article  CAS  PubMed  Google Scholar 

  • Ogawa H, Ishiguro Y, Fujioka M (1983) Guanidoacetate methyltransferase from rat liver: purification, properties, and evidence for the involvement of sulfhydryl groups for activity. Arch Biochem Biophys 226:265–275

    Article  CAS  PubMed  Google Scholar 

  • Pilz S, Tomaschitz A, Meinitzer A, Drechsler C, Ritz E, Krane V, Wanner C, Böhm BO, März W (2011a) Low serum homoarginine is a novel risk factor for fatal strokes in patients undergoing coronary angiography. Stroke 42:1132–1134

    Article  CAS  PubMed  Google Scholar 

  • Pilz S, Meinitzer A, Tomaschitz A, Drechsler C, Ritz E, Krane V et al (2011b) Low homoarginine concentration is a novel risk factor for heart disease. Heart 97:1127–1222

    Article  Google Scholar 

  • Pilz S, Teerlink T, Scheffer PG, Meinitzer A, Rutters F, Tomaschitz A, Drechsler C, Kienreich K, Nijpels G, Stehouwer CD, März W, Dekker JM (2014) Homoarginine and mortality in an older population: the Hoorn study. Eur J Clin Invest 44:200–208

    Article  CAS  PubMed  Google Scholar 

  • Pilz S, Meinitzer A, Gaksch M, Grübler M, Verheyen N, Drechsler C, Hartaigh BÓ, Lang F, Alesutan I, Voelkl J, März W, Tomaschitz A (2015a) Homoarginine in the renal and cardiovascular systems. Amino Acids. doi:10.1007/s00726-015-1993-2

    Google Scholar 

  • Pilz S, Putz-Bankuti C, Meinitzer A, März W, Kienreich K, Stojakovic T, Pieber TR, Stauber RE (2015b) Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease. Amino Acids. doi:10.1007/s00726-015-2000-7

    Google Scholar 

  • Roberts JJ, Walker JB (1985) Higher homolo and N-ethyl analog of creatine as synthetic phosphagen precursors in brain, heart, and muscle, repressors of liver amidinotransferase, and substrates for creatine catabolic enzymes. J Biol Chem 260:13502–13508

    CAS  PubMed  Google Scholar 

  • Ryan WL, Wells IC (1964) Homocitrulline and homoarginine synthesis from lysine. Science 144:1122–1127

    Article  CAS  PubMed  Google Scholar 

  • Ryan WL, Barak AJ, Johnson RJ (1968) Lysine, homocitrulline, and homoarginine metabolism by the isolated perfused rat liver. Arch Biochem Biophys 123:294–297

    Article  CAS  PubMed  Google Scholar 

  • Ryan WL, Johnson RJ, Dimari S (1969) Homoarginine synthesis by rat kidney. Arch Biochem Biophys 131:521–526

    Article  CAS  PubMed  Google Scholar 

  • Schmidt A, Marescau B, Boehm EA, Renema WK, Peco R, Das A et al (2004) Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet 13:905–921

    Article  CAS  PubMed  Google Scholar 

  • Siroen MP, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PA (2006) The clinical significance of asymmetric dimethylarginine. Annu Rev Nutr 26:203–228

    Article  CAS  PubMed  Google Scholar 

  • Takata Y, Date T, Fujioka M (1991) Rat liver guanidinoacetate methyltransferase. Proximity of cysteine residues at positions 15, 90 and 219 as revealed by site-directed mutagenesis and chemical modification. Biochem J 277(Pt 2):399–406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Teerlink T, Luo Z, Palm F, Wilcox CS (2009) Cellular ADMA: regulation and action. Pharmacol Res 60:448–460

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tomaschitz A, Meinitzer A, Pilz S, Rus-Machan J, Genser B, Drechsler C et al (2014) Homoarginine, kidney function and cardiovascular mortality risk. Nephrol Dial Transplant 29:663–671

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D (2009) De novo synthesis of trideuteromethyl esters of amino acids for use in GC- MS and GC-tandem MS exemplified for ADMA in human plasma and urine: standardization, validation, comparison and proof of evidence for their aptitude as internal standards. J Chromatogr B 877:2308–2320

    Article  CAS  Google Scholar 

  • Tsikas D, Kayacelebi AA (2014) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2092–2093

    Article  Google Scholar 

  • Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000) Endogenous nitric oxide synthase inhibitors are responsible for the Arginine paradox. FEBS Lett 478:1–3

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frölich JC (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B 798:87–99

    Article  CAS  Google Scholar 

  • Tsikas D, Wolf A, Mitschke A, Gutzki FM, Will W, Bader M (2010) GC–MS determination of creatinine in human biological fluids as pentafluorobenzyl derivative in clinical studies and biomonitoring: inter-laboratory comparison in urine with Jaffé, HPLC and enzymatic assays. J Chromatogr B 878:2582–2592

    Article  CAS  Google Scholar 

  • Tsikas D, Beckmann B, Gutzki FM, Jordan J (2011) Simultaneous gas chromatography-tandem mass spectrometry quantification of symmetric and asymmetric dimethylarginine in human urine. Anal Biochem 413:60–62

    Article  CAS  PubMed  Google Scholar 

  • Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JS et al (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884

    Article  CAS  PubMed  Google Scholar 

  • van der Zwan LP, Davids M, Scheffer PG, Dekker JM, Stehouver CDA, Teerlink T (2013) l-Homoarginine and arginine are antagonistically related to blood pressure in an elderly population: the Hoorn study. J Hypertens 31:1114–1123

    Article  PubMed  Google Scholar 

  • Walker JB, Hannan JK (1976) Creatine biosynthesis during embryonic development. False feedback suppression of liver amidinotransferase by N-acetimidoylsarcosine and 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine). Biochemistry 15:2519–2522

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Cudd TA, Jobgen WS, Kim SW, Lassala A, Li P, Matis JH, Meininger CJ, Spencer TE (2007) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137(6 Suppl 2):1673S–1680S

    CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J et al (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213

    CAS  PubMed  Google Scholar 

  • Yang Y, Wu Z, Jia S, Dahanayaka S, Feng S, Meininger CJ, McNeal CJ, Wu G (2015) Safety of long-term dietary supplementation with l-arginine in rats. Amino Acids. doi:10.1007/s00726-015-1992-3

    Google Scholar 

  • Yin J, Ren W, Hou Y, Wu M, Xiao H, Duan J, Zhao Y, Li T, Yin Y, Wu G, Nyachoti CM (2015) Use of homoarginine for measuring true ileal digestibility of amino acids in food protein. Amino Acids. doi:10.1007/s00726-015-1958-5

    Google Scholar 

  • Yuile CL, Lampson BG, Miller LL, Whipple GH (1951) Conversion of plasma protein to tissue protein without evidence of protein breakdown; results of giving plasma protein labeled with carbon 14 parenterally to dogs. J Exp Med 93:539–557

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

    Authors and Affiliations

    1. Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30623, Hannover, Germany

      Arslan Arinc Kayacelebi, Kristine Chobanyan-Jürgens, Jessica Y. Schneider, Sabine Rothmann, Jürgen C. Frölich & Dimitrios Tsikas

    2. Department of Neuropaediatrics, University Children’s Hospital, Ruhr University, Bochum, Germany

      Jennifer Langen, Katharina Weigt-Usinger & Thomas Lücke

    3. INRA, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, 75005, Paris, France

      François Mariotti & Jean François Huneau

    4. AgroParisTech, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, 75005, Paris, France

      François Mariotti & Jean François Huneau

    5. Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Dorothee Atzler & Edzard Schwedhelm

    6. DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany

      Dorothee Atzler & Edzard Schwedhelm

    7. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Chi-un Choe

    8. Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Chi-un Choe

    Authors
    1. Arslan Arinc Kayacelebi
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jennifer Langen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Katharina Weigt-Usinger
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Kristine Chobanyan-Jürgens
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. François Mariotti
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jessica Y. Schneider
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Sabine Rothmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jürgen C. Frölich
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Dorothee Atzler
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Chi-un Choe
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Edzard Schwedhelm
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Jean François Huneau
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Thomas Lücke
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Dimitrios Tsikas
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Dimitrios Tsikas.

    Additional information

    A. A. Kayacelebi and J. Langen contributed equally to this work.

    T. Lücke and D. Tsikas are joint senior authors.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Kayacelebi, A.A., Langen, J., Weigt-Usinger, K. et al. Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free l-arginine in humans. Amino Acids 47, 1893–1908 (2015). https://doi.org/10.1007/s00726-015-2012-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00726-015-2012-3

    Keywords

    Search

    Navigation