4,4-Difluorinated analogues of l-arginine and NG-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase |
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| Authors: | Nathaniel I Martin Joshua J Woodward Michael B Winter Michael A Marletta |
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| Institution: | 1. Department of Medicinal Chemistry and Chemical Biology, University of Utrecht, 3584 CA, The Netherlands;2. Department of Chemistry, University of California, 556 Stanley Hall, Berkeley, CA 94720-3220, USA;3. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA;4. Division of Physical Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA |
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| Abstract: | 4,4-Difluoro-l-arginine and 4,4-difluoro-NG-hydroxy-l-arginine were synthesized and shown to be substrates for the inducible isoform of nitric oxide synthase (iNOS). Binding of both fluorinated analogues to the NOS active site was also investigated using a spectral binding assay employing a heme domain construct of the inducible NOS isoform (iNOSheme). 4,4-Difluoro-NG-hydroxy-arginine was found to bind at the NOS active site in a unique manner consistent with a model involving ligation of the FeIII heme center by the oxygen atom of the NG-hydroxy moiety. |
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