Inducible nitric oxide synthase: Identification of amino acid residues essential for dimerization and binding of tetrahydrobiopterin Academic Article Article uri icon

Overview

MeSH Major

  • Anti-Bacterial Agents
  • Biomedical Research
  • Drug Design
  • Drug Industry
  • Marketing
  • Research Support as Topic

abstract

  • Nitric oxide synthases (NOSs) require tetrahydrobiopterin (BH4) for dimerization and NO production. Mutation analysis of mouse inducible NOS (iNOS; NOS2) identified Gly-450 and Ala-453 as critical for NO production, dimer formation, and BH4 binding. Substitutions at five neighboring positions were tolerated, and normal binding of heme, calmodulin, and NADPH militated against major distortions affecting the NH2-terminal portion, midzone, or COOH terminus of the inactive mutants. Direct involvement of residues 450 and 453 in the binding of BH4 is supported by the striking homology of residues 448-480 to a region extensively shared by the three BH4-utilizing aromatic amino acid hydroxylases and is consistent with the conservation of these residues among all 10 reported NOS sequences, including mammalian NOSs 1, 2, and 3, as well as avian and insect NOSs. Altered binding of BH4 and/or L-arginine may explain how the addition of a single methyl group to the side chain of residue 450 or the addition of three methylenes to residue 453 can each abolish an enzymatic activity that reflects the concerted function of 1143 other residues.

publication date

  • December 5, 1995

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1073/pnas.92.25.11514

PubMed ID

  • 8524794

Additional Document Info

start page

  • 11514

end page

  • 8

volume

  • 92

number

  • 25