Dimethylarginine‐Dimethylaminohydrolase‐2 (DDAH‐2) Does Not Metabolize Methylarginines

Abstract

Free endogenous methylarginines, N(ω)-monomethyl-L-arginine (L-NMMA) and N(ω),N(ω')-dimethyl-L-arginine (ADMA), inhibit NO synthases (NOSs) and are metabolized by dimethylargininedimethylaminohydrolase (DDAH). A postulated metabolism has been shown several times for DDAH-1, but the involvement of DDAH-2 in the degradation of ADMA and L-NMMA is still a matter of debate. Determination of the isoform-specific DDAH protein expression profiles in various porcine tissue types shows a correlation of DDAH activity only with DDAH-1 levels. DDAH activity (measured as L-citrulline formation from the conversion of methylarginines and alternative DDAH substrates) was detected in DDAH-1-rich porcine tissue types, that is, kidney, liver, and brain, but not in DDAH-2-rich porcine fractions, that is, spleen and thyroid. Furthermore, several ex vivo studies showed DDAH activity to be important for L-citrulline formation in porcine tissue and indicated the absence of an endogenous DDAH inhibitor in porcine tissue. This study provides new insights into tissue distributions as well as substrate selectivity for both DDAH isoforms. Although DDAH-1 is known to metabolize the endogenous NOS inhibitors L-NMMA and ADMA, a physiological function for DDAH-2 has yet to be determined. Hence, determining DDAH activity by methylarginine conversion is not suitable for analyzing isoform selectivity of DDAH-1 inhibitors as postulated.

Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers

“…For example, in addition to the brain, DDAH1 is known to express in the pancreas, skeletal muscle, heart, liver, and kidneys. Recent genetic [ 10 ] and biochemical [ 11 ] studies report that DDAH1 is mainly responsible for the enzymatic breakdown of ADMA into citrulline and methylamine. The clearance of ADMA by DDAH is however compromised by several cardiovascular risk factors that impair the expression and/or activity of DDAH [ 8 ].…”

Pharmacokinetic Characterization of the DDAH1 Inhibitors ZST316 and ZST152 in Mice Using a HPLC-MS/MS Method

“…The isoform 1 of the enzyme dimethylarginine dimethylaminohydrolase (DDAH1) plays a critical role in the metabolism of the endogenous methylated arginines, asymmetric N G ,N G -dimethyl-L-arginine (ADMA) and N G -monomethyl-L-arginine (NMMA), into L-citrulline and dimethylamine [ 1 , 2 , 3 ]. As both ADMA and NMMA are potent endogenous inhibitors of the three isoforms of nitric oxide (NO) synthase (NOS), DDAH1 regulation significantly influences NO synthesis [ 4 , 5 ].…”

Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development

“…DDAH-2 appears prevalent in pancreatic islet cells [5] and infected tissues [6]. In addition, Altman et al reported a study showing high expression of DDAH-2 in porcine immune tissues [7]. The two isoforms are both expressed in kidney [8,9,10], heart [11,12], adipose tissue [13], placenta and trophoblasts [14], and the liver [15,16,17,18].…”