FIGURE 1 | The ADMA–DDAH–NOS pathway.

From the following article:

The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis

James Leiper & Manasi Nandi

Nature Reviews Drug Discovery 10, 277-291 (April 2011)

doi:10.1038/nrd3358

The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis

Mammalian nitric oxide (NO) synthesis is catalysed by three isoforms of nitric oxide synthase (NOS) that have different tissue distributions: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). L-arginine is the substrate for all three isoforms of NOS. Following their incorporation into proteins, L-arginine residues that lie within certain sequences can be methylated by protein arginine methyltransferases. Proteolysis of arginine-methylated proteins releases free methylarginines into the cytosol. The asymmetrically methylated arginines (ω-NG,NG-asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (L-NMMA)) are competitive inhibitors of all NOS isoforms. Asymmetric methylarginines are predominantly removed via their metabolism, which is catalysed by dimethylarginine dimethylaminohydrolase (DDAH) enzymes, and to a lesser extent by renal excretion. DDAH enzymes may exert physiological effects via NOS-independent pathways, such as regulation of vascular endothelial growth factor (VEGF) expression. EDRF, endothelium-derived relaxing factor; SMC, smooth muscle cell.

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