A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

Abstract

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

Asymmetric Dimethylarginine Enables Depolarizing Spikes and Vasospasm in Mesenteric and Coronary Resistance Arteries

“…412W also reversed the loss of endothelium-dependent (NO) vasorelaxation in human saphenous artery. 17 , 30 Both effects demonstrate continual turnover of methylarginines, with DDAH1 ensuring the intracellular ADMA accumulation is not normally sufficient to block NO synthesis. We used the recently developed and selective DDAH1 inhibitor, L-257, which binds within the active site of the enzyme elevating ADMA sufficiently to inhibit NO signaling.…”

Arginine metabolomics in mood disorders

“…1 ) [ 68 , 69 ]. After protein degradation, ADMA is either transformed to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolase 1 (DDAH1) or transported into the extracellular compartment for remote DDAH1 metabolism or renal elimination [ 30 , [70] , [71] , [72] , [73] ]. Differently from ADMA, SDMA is not metabolised by DDAH1 and undergoes renal elimination [ 28 , 71 , 74 ].…”

Recent advances in DDAH1 inhibitor design and discovery: insights from structure–activity relationships and X-ray crystal structures

“…Recently, we demonstrated that DDAH2 does not metabolize ADMA and may have an ADMA independent function. 15 Given previously known DDAH inhibitors were based on inhibiting ADMA conversion to citrulline, it is likely these compounds inhibit DDAH1 only.…”