A molecular perspective on dimethylarginine dimethylaminohydrolases structure and function

Nitric oxide (NO) is a central signaling molecule that regulates vascular tone, neurotransmission, and immune function. NO production from L-arginine by nitric oxide synthase (NOS) must be tightly controlled, as excess NO contributes to oxidative and nitrosative stress. Asymmetric dimethylarginine (ADMA) and monomethylarginine (L-NMMA) are endogenous NOS inhibitors whose accumulation leads to cardiovascular, renal, and neurodegenerative diseases. Dimethylarginine dimethylaminohydrolase (DDAH) converts ADMA and NMMA to L-citrulline and dimethylamine or monomethylamine, respectively, thereby controlling NO bioavailability. Two DDAH isoforms are present in humans, namely, DDAH1 and DDAH2. DDAH1 has a demonstrated role in the catabolism of ADMA, while DDAH2 appears to be functionally divergent, playing potential regulatory and signaling roles. Structural analyses reveal that, despite a conserved α/β-propeller architecture, the different biochemical properties of the two isoforms depend on key amino acid substitutions within the active site. Dysregulation of DDAH1 leads to pathological ADMA accumulation, linking impaired enzyme function to endothelial dysfunction and oxidative stress. Consequently, DDAH1 represents an emerging therapeutic target, and several substrate analogues, small molecules, and natural ligands have been identified as inhibitors. On the other hand, the assessment of DDAH2 function is still to be defined. The present review summarizes current molecular, biochemical, and structural insights into DDAH isoforms and discusses their potential as pharmacological targets for diseases associated with altered NO signaling.