N,N-dimethylarginine dimethylaminohydrolase 1 (DDAH1)

N,N-dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a critical enzyme that regulates the bioavailability of nitric oxide (NO) by metabolizing asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) (UniProt P55032). These methylated arginines are endogenous inhibitors of nitric oxide synthase (NOS), and their accumulation can lead to reduced NO production and subsequent endothelial dysfunction (PubMed 21493918). DDAH1 is primarily expressed in the liver and kidneys, where it maintains homeostatic levels of ADMA, thereby supporting vascular health and blood pressure regulation (PubMed 21493918). In pathological states such as cardiovascular disease and chronic kidney disease, DDAH1 activity is often impaired, contributing to hypertension and oxidative stress (PubMed 3132073). Conversely, DDAH1 is frequently upregulated in various cancers, where it promotes tumor growth, migration, and angiogenesis through the overproduction of NO (PubMed 35146014). Consequently, DDAH1 is a versatile therapeutic target; inhibitors like L-257 and DD1E5 are being explored to suppress tumor progression and treat sepsis, while activators or expression enhancers like ursodeoxycholic acid are investigated for their potential to restore NO signaling in cardiovascular and metabolic disorders (PubMed 17135234, 30673234).

Other names

Dimethylarginine dimethylaminohydrolase 1DDAH-1DDAHIDimethylargininase-1N(G),N(G)-dimethylarginine dimethylaminohydrolase 1NG,NG-dimethylarginine dimethylaminohydrolase 1Epididymis secretory protein Li 16HEL-S-16

DDAH1 inhibitors competitively bind to the enzyme's active site to prevent the hydrolysis of asymmetric dimethylarginine (ADMA), leading to its accumulation and the subsequent inhibition of nitric oxide synthase (NOS), which reduces nitric oxide (NO) production. Alternatively, agents such as farnesoid X receptor (FXR) agonists can upregulate DDAH1 expression to enhance ADMA degradation and restore NO bioavailability in conditions of endothelial dysfunction.