Electron Paramagnetic Resonance Spectroscopy of the Heme Domain of Inducible Nitric Oxide Synthase: Binding of Ligands at the Arginine Site Induces Changes in the Heme Ligation Geometry

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Abstract
The electron paramagnetic resonance spectra of the heme domain of inducible nitric oxide synthase (iNOS) demonstrate a close relationship to the corresponding spectra of the neuronal isoform (nNOS). The binding of ligands to the iNOS arginine site perturbs the environment of the high-spin ferriheme in a highly ligand-specific manner. The iNOS forms five-coordinate, high-spin complexes with arginine analogs which are clearly related to the corresponding complexes of nNOS. Studies indicate that the binding of l-arginine, Nω-hydroxy-l-arginine (NHA), and Nω-methyl-l-arginine (NMA) produces various spectroscopic species closely corresponding to the equivalent complexes of nNOS, while Nω-nitro-l-arginine (NNA) binding produces a state which appears intermediate in character between the nNOS NNA and arginine complexes. These spectroscopic studies have permitted the determination of ligand-specific high-spin states which reveal similarities and differences between iNOS and nNOS.