COMPUTER-AIDED COMPARISON OF THE INHIBITION OF ARGINASE AND NITRIC-OXIDE SYNTHASE IN MACROPHAGES BY AMINO-ACIDS NOT RELATED TO ARGININE

Macrophages contain arginase and an inducible nitric oxide (NO) syntha se that use the same substrate, L-arginine, to produce nitric oxide an d urea, respectively, Arginase was inhibited by various amino acids no t related to L-arginine. These compounds were bound to the substrate b inding site of the enzyme as supported by kinetic studies. Five bindin g sites were defined in this area by computer-aided analysis, and thre e complementary sires in a compound were sufficient to give an inhibit ory character. NO synthase could nor be inhibited by these compounds, but certain derivatives (e.g., putrescine or L-valinol) caused a marke d and probably allosteric inhibition. The possible biological importan ce of these inhibitions in the tumoricid function of macrophages is di scussed.