Redefining the biological and pathophysiological role of dimethylarginine dimethylaminohydrolase 2

The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 metabolizes asymmetric dimethylarginine (ADMA), a critical endogenous cardiovascular risk factor. In the past two decades, there has been significant controversy about whether DDAH2, the other DDAH isoform, is also able to directly metabolize ADMA. There has been evidence that DDAH2 regulates several critical processes involved in cardiovascular and immune homeostasis. However, the molecular mechanisms underpinning these effects are unclear. In this opinion, we discuss the previous and current knowledge of ADMA metabolism by DDAH in light of a recent consortium study, which convincingly demonstrated that DDAH2 is not capable of metabolizing ADMA, unlike DDAH1. Thus, further research in this field is needed to uncover the molecular mechanisms of DDAH2 and its role in various disorders.