Studies on the Formation of Dimethylamine and its Metabolic Fate in Higher Animals

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A new enzyme, N^G, N^G-dimethylarginine dimethylaminohydrolase which plays a role in the metabolism of N^G, N^G-dimethyl-L-arginine (DMA), has been purified to homogeneity from rat kidney. The enzyme consists of a single polypeptide and its molecular weight is about 33,000. The pI of the enzyme is at pH 5.2. The enzyme catalyzes the hydrolytic liberation of the dimethyl-amino moiety of DMA and forms L-cirulline and dimethylamine. It is highly specific for DMA and N^G-monomethyl-L-arginine (MMA), and Km values for these amino acids are 0.18 and 0.36 mM, respectively. The enzyme shows the maximum activity at pH 6.5 and requires on co-factor. The activity is strongly inhibited by SH-blocking reagents and divalent metal ions. The monoclonal antibody against the purified enzyme was prepared from the BALB/c mouse and used for the analyze of the distribution of the enzyme. Both the enzyme activity and protein were found in various tissues of male and female rats, suggesting that DMA and MMA liberated in body fluids may readily hydrolyzed by this enzyme to form L-citrulline and dimethylamine or monomethylamine. The liberation of dimethylamine from DMA in various tissues was demonstrated isotopically and about 90% of the dimethylamine liberated was readily excreted in urne without further degradation. Trace amounts of dimethylamine were metabolized to urea and unidentified acidic or neutral compounds. It remains still unclear whether the trace metabolites containnitrosodimethylamine. The results of this experiment shows that the enzyme catabolizes the blockers of Endotherium-Derived Relaxing Factor (EDRF), DMA and MMA. This fact may prompt the further investigation on the relationship between the role of this enzyme and the regulation of EDRF-production from endotherial cells.