Figure 1

Methylarginine metabolism. Protein arginine methylation is performed by a class of enzymes termed protein arginine methyltransferases (PRMT), which specifically methylate protein-incorporated L-arginine (L-Arg) residues to generate protein-incorporated monomethylarginine (L-MMA), asymmetric dimethylarginine (ADMA), or symmetric dimethylarginine (SDMA). Upon proteolytic cleavage of arginine-methylated proteins, free intracellular MMA, ADMA, or SDMA are generated. Free L-Arg can be metabolized by arginases to L-ornithine and urea, or by nitric oxide synthases (NOS) to NO and L-citrulline. Free methylarginines can also be released to the extracellular space by cationic amino acid transporters (CAT) to induce distinct biological effects, undergo hepatic metabolism, or renal excretion. MMA and ADMA, but not SDMA can be converted to L-citrulline and mono- or diamines by a class of intracellular enzymes called dimethylarginine dimethylaminohydrolases (DDAH). Most importantly, MMA and ADMA, but not SDMA, act as potent endogenous inhibitors of NOS enzymes.