Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)

Abstract

Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) are toxic, non-proteinogenic amino acids formed by post-translational modification and are uremic toxins that inhibit nitric oxide (NO) production and play multifunctional roles in many human diseases. Both ADMA and SDMA have emerged as strong predictors of cardiovascular events and death in a range of illnesses. Major progress has been made in research on ADMA-lowering therapies in animal studies; however, further studies are required to fill the translational gap between animal models and clinical trials in order to treat human diseases related to elevated ADMA/SDMA levels. Here, we review the reported impacts of ADMA and SDMA on human health and disease, focusing on the synthesis and metabolism of ADMA and SDMA; the pathophysiological roles of these dimethylarginines; clinical conditions and animal models associated with elevated ADMA and SDMA levels; and potential therapies against ADMA and SDMA. There is currently no specific pharmacological therapy for lowering the levels and counteracting the deleterious effects of ADMA and SDMA. A better understanding of the mechanisms underlying the impact of ADMA and SDMA on a wide range of human diseases is essential to the development of specific therapies against diseases related to ADMA and SDMA.

Keywords: alanine‐glyoxylate aminotransferase‐2; chronic  kidney disease; dimethylarginine dimethylaminohydrolase; nitric  oxide; nonproteinogenic amino acid; asymmetric dimethylarginine; cardiovascular  disease; protein arginine methyltransferase; symmetric dimethylarginine; uremic  toxins.

Figure 1

Schema outlining the synthesis and metabolism of ADMA and SDMA. Protein arginine (purple circle) methylation is performed by a family of enzymes termed protein arginine methyltransferases (PRMTs), which methylate protein-incorporated l-arginine residues to generate protein-incorporated N^G monomethyl-l-arginine (NMMA; blue circle). Type I PRMTs generate asymmetric dimethylarginine (ADMA; black circle) and type II PRMTs convert NMMA to symmetric dimethylarginine (SDMA; red circle). Protein-incorporated l-arginine residues can also be converted to citrulline (yellow circle) by peptidylarginine deaminases (PADs), thereby blocking methylation on the arginine residue. Upon proteolytic cleavage of arginine-methylated proteins, free ADMA and SDMA are released into the cytoplasm. ADMA and SDMA can be moved out of the cells via cationic amino acid transporter (CAT) and transported to other organs or excreted in urine. ADMA can be converted to l-citrulline and dimethylamine by dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and -2 (DDAH-2). Alanine-glyoxylate aminotransferase 2 (AGXT2), a mitochondrial aminotransferase expressed primarily in the kidney, can metabolize ADMA as well as SDMA. ADMA can be transaminated by the enzyme AGXT2 to α-keto-δ-(N^G,N^G-dimethylguanidino) valeric acid (DMGV).