How is ADMA synthesized in the body?

Dimethylarginines are formed during proteolysis of methylated proteins. Protein methylation is a ubiquitously present mechanism of post-translational modification of proteins. It results in a modification of the tertiary structure and the function of proteins. This process is catalyzed by a group of enzymes named S-adenosylmethionine protein N-methyltransferases (protein methylases I and II) [10]. The complex name of these enzymes suggests their molecular function: They transfer one or more methyl groups from the methyl group donor S-adenosylmethionine to L-arginine residues within proteins or polypeptides.

Figure 3. When cultured human endothelial cells are incubated with (14C-methyl) labelled S-adenosylmethionine (SAM; an intermediate product of homocysteine metabolism), the radioactively labelled methyl group is being transferred onto ADMA. The graph shows the chromato-graphic separation of a cell culture supernatant with subsequent scintillation counting of HPLC fractions after incubation with 14C-SAM. This experiment demonstrates the existence of a metabolic link between the homocysteine and ADMA pathways (from [11] with kind permission of the publishers).

Accordingly, depending on the number of transferred methyl groups, NG-monomethyl-L-arginine and NG, NG-dimethyl-L-arginine (asymmetric dimethylarginine) are formed by the activity of protein methylase I, and NG-monomethyl-L-arginine and NG, NG`-L-arginine (symmetric dimethylarginine) are formed by the activity of protein methylase II. Free circulating ADMA and SDMA are then released after degradation of such methylated protein residues.
Methyl groups contained in dimethylarginines are derived from the ubiquitously available methyl group donor S-adenosylmethionine, an intermediate in the metabolism of homocysteine. This is experimentally proven: When cultured human endothelial cells are incubated with radioactively labelled S-[14C]-adenosylmethionine, part of this radioactivity can be detected within newly synthesized ADMA (Figure 3) [11]. Interestingly, this finding may provide an explanation to the mechanism by which homo-cysteine impairs endothelial function in animals and humans.