Nitric oxide synthase (NOS) isoforms catalyze the conversion of L-arginine to L-citrulline and nitric oxide.  N5-(1-iminoethyl)-L-ornithine (L-NIO), an amidine-containing molecule, is an inactivator of inducible NOS.  A mechanism for the formation of a-meso-hydroxyheme during amidine inactivation of inducible NOS has been proposed.  This implicates a new and general regulation mechanism for heme-containing enzymes: an irreversible enzyme inactivation without inactivator modification.  Herein, we attempt to find support for this previously proposed mechanism through the design and synthesis of a series of L-NIO and N-(3-(Aminomethyl)benzyl)acetamidine (1400W) analogues.  It was found that L-NIO has dual biological functions as an inactivator and substrate.  We disclose the exploration of this proposed dual binding mode of L-NIO by derivative design.  Furthermore, this work explores heme regulation, which could be applied to other biologically significant heme enzymes.

Mechanism of inactivation of inducible nitric oxide synthase by amidines

243rd National Meeting (2012)

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