Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency

Jeffrey D. Martell, Huiying Li, Tzanko Doukov, Pavel Martásek, Linda J. Roman, Michael Soltis, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The heme-thioether ligand interaction often occurs between heme iron and native methionine ligands, but thioether-based heme-coordinating (type II) inhibitors are uncommon due to the difficulty in stabilizing the Fe-S bond. Here, a thioether-based inhibitor (3) of neuronal nitric oxide synthase (nNOS) was designed, and its binding was characterized by spectrophotometry and crystallography. A crystal structure of inhibitor 3 coordinated to heme iron was obtained, representing, to our knowledge, the first crystal structure of a thioether inhibitor complexed to any heme enzyme. A series of related potential inhibitors (4-8) also were evaluated. Compounds 4-8 were all found to be type I (non-heme-coordinating) inhibitors of ferric nNOS, but 4 and 6-8 were found to switch to type II upon heme reduction to the ferrous state, reflecting the higher affinity of thioethers for ferrous heme than for ferric heme. Contrary to what has been widely thought, thioether-heme ligation was found not to increase inhibitor potency, illustrating the intrinsic weakness of the thioether-ferric heme linkage. Subtle changes in the alkyl groups attached to the thioether sulfur caused drastic changes in the binding conformation, indicating that hydrophobic contacts play a crucial role in stabilizing the thioether-heme coordination.

Original languageEnglish (US)
Pages (from-to)798-806
Number of pages9
JournalJournal of the American Chemical Society
Volume132
Issue number2
DOIs
StatePublished - Jan 20 2010

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency'. Together they form a unique fingerprint.

Cite this