Introduction

Dimethylarginine Dimethyaminohydrolase (commonly known as DDAH) is a member of the hydrolase family of enzymes which use water to break down molecules (palm). Specifically, DDAH is a nitric oxide synthase (NOS) regulator. Its metabolizes free arginine derivatives, namely NѠ,NѠ-dimethyl-L-arginine (ADMA) and NѠ-methyl-L-arginine (MMA) which competitively inhibit NOS ^[1]. DDAH is expressed in the cytosol of cells in humans, mice, rates, sheep, cattle, and bacteria ^[2]. DDAH activity has been localized mainly to the brain, kidney, pancreas, and liver in these organisms. If DDAH is overexpressed, NOS can be activated ^[3]. ADMA and MMA can inhibit the synthesis of NO by competitively inhibiting all three kinds of NOS (endothelial, neuronal, and inducible) ^[3]. Underexpression or inhibition of DDAH decreases NOS activity and NO levels will decrease. Because of nitric oxide’s (NO) role in signaling and defense, NO levels in an organism must be regulated to reduce damage to cells ^[4]. This suggests that the rate-limiting step of this reaction is not the lid movement but is the actual chemistry happening to the substrate in the active site of DDAH ^[5]. The specific residues in the lid region are different in different organisms ^[3]. The only consistent similarity is a conserved leucine residue in this lid that function to hydrogen bond with the ligand bound to the active site ^[5]. Different isoforms from the same species can have differences in lid regions as well ^[3]. DDAH-2 has a negatively charged lid while DDAH-1 has a positively charged lid ^[3].

Active Site

The normal DDAH regulation mechanism depends on the presence of Cys249 in the active site that acts as a nucleophile in the mechanism ^[6]