Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond

Abstract

Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway.

Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients

“…MMA, ADMA, SDMA and DMA circulate in blood at nM-to-µM concentrations and are excreted in the urine (Tsikas 2008 ; Martens-Lobenhoffer and Bode-Böger 2014 ). In adults, up to 90% of daily produced ADMA is estimated to be hydrolyzed to DMA, with the remaining 10% of ADMA being excreted unchanged in the urine (Tsikas 2020 ). Thus, urinary DMA is the major urinary metabolite of ADMA in humans.…”

“…Measurement of major urinary metabolites of circulating precursors is a widely used non-invasive approach to estimate their whole-body synthesis of endogenous substances such as DMA (Achan et al 2003 ; Tsikas 2020 and references therein), nitrate (Baylis and Vallance 1998 ), prostaglandins (Ferretti et al 1983 ), thromboxane (Roberts et al 1977 ), leukotrienes (reviewed in Tsikas 1998 ), RNA (Sander et al 1986 ), and catecholamines (Duncan et al 1988 ). Recently, we proposed such a method to measure whole-body PADiMe activity in humans and demonstrated its utility in human studies (Bollenbach et al 2019 ; Bollenbach et al 2020a , b ).…”

Diminished Systemic Amino Acids Metabolome and Lipid Peroxidation in Ureteropelvic Junction Obstruction (UPJO) Infants Requiring Surgery

“…The methylation of protein-bound arginine forms the endogenous arginine analogue ADMA [ 47 ]. Both ADMA and its stereoisomer, symmetric dimethylarginine (SDMA), are excreted in urine, while only ADMA is subjected to hydrolytic degradation to citrulline and dimethylamine in the kidney or in the liver [ 48 , 49 ].…”

“…Both ADMA and its stereoisomer, symmetric dimethylarginine (SDMA), are excreted in urine, while only ADMA is subjected to hydrolytic degradation to citrulline and dimethylamine in the kidney or in the liver [ 48 , 49 ]. The altered dimethylamine that was found to be different between the studied groups in our previous study [ 10 ] could also be linked to choline as a breakdown product via its formation to trimethylamine [ 45 , 47 , 50 ].…”

Local and Systemic Alterations of the L-Arginine/Nitric Oxide Pathway in Sputum, Blood, and Urine of Pediatric Cystic Fibrosis Patients and Effects of Antibiotic Treatment

“…ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to produce dimethylamine (DMA) and L-citrulline [18,19]. DMA in urine is a useful measure of whole-body DDAH activity [20]. The sum of urinary ADMA and DMA (i.e., ADMA + DMA) represents the whole-body asymmetric dimethylation of Arg residues in proteins.…”