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) synthase that use the same substrate, L-arginine, to produce nitric oxide and urea, respectively. Arginase was inhibited by various amino acids not related to L-arginine. These compounds were bound to the substrate binding site of the enzyme as supported by kinetic studies. Five binding sites were defined in this area by computer-aided analysis, and three complementary sites in a compound were sufficient to give an inhibitory character. NO synthase could not be inhibited by these compounds, but certain derivatives (e.g., putrescine or L-valinol) caused a marked and probably allosteric inhibition. The possible biological importance of these inhibitions in the tumoricid function of macrophages is discussed.