title: Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans.
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.
authors.affiliation: Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30623, Hannover, Germany.
authors.forename: Arslan Arinc
authors.initials: AA
authors.lastname: Kayacelebi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Langen
authors.forename: Katharina
authors.initials: K
authors.lastname: Weigt-Usinger
authors.forename: Kristine
authors.initials: K
authors.lastname: Chobanyan-Jürgens
authors.forename: François
authors.initials: F
authors.lastname: Mariotti
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Schneider
authors.forename: Sabine
authors.initials: S
authors.lastname: Rothmann
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Frölich
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Chi-Un
authors.initials: CU
authors.lastname: Choe
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Jean François
authors.initials: JF
authors.lastname: Huneau
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
mesh_terms: D000293:Adolescent; D000328:Adult; D000579:Amidinotransferases / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002648:Child; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D002658:Developmental Disabilities / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D050937:Guanidinoacetate N-Methyltransferase / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006709:Homoarginine / Q000096:biosynthesis*; D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D007805:Language Development Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009069:Movement Disorders / Q000097:blood / Q000151:congenital / Q000188:drug therapy / Q000235:genetics; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D013064:Speech Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics
chemical_list: D006709:Homoarginine; C018524:N,N-dimethylarginine; D001120:Arginine; C494506:GAMT protein, human; C494507:Gamt protein, mouse; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase