Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation

Crystal M. Cordes, Robert G. Bennett, Gerri L. Siford, Frederick G. Hamel

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Insulin-degrading enzyme (IDE) is responsible for the degradation of a number of hormones and peptides, including insulin and amyloid β (Aβ). Genetic studies have linked IDE to both type 2 diabetes and Alzheimer's disease. Despite its potential importance in these diseases, relatively little is known about the factors that regulate the activity and function of IDE. Protein S-nitrosylation is now recognized as a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe a mechanism of inactivation of IDE by NO. NO donors decreased both insulin and Aβ degrading activities of IDE. Insulin-degrading activity appeared more sensitive to NO inhibition than Aβ degrading activity. IDE-mediated regulation of proteasome activity was affected similarly to insulin-degrading activity. We found IDE to be nitrosylated in the presence of NO donors compared to that of untreated enzyme and the control compound. S-nitrosylation of IDE enzyme did not affect the insulin degradation products produced by the enzyme, nor did NO affect insulin binding to IDE as determined by cross-linking studies. Kinetic analysis of NO inhibition of IDE confirmed that the inhibition was noncompetitive. These data suggest a possible reversible mechanism by which inhibition of IDE under conditions of nitrosative stress could contribute to pathological disease conditions such as Alzheimer's disease and type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)1064-1073
Number of pages10
JournalBiochemical Pharmacology
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2009

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Insulysin
  • Proteasome
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation'. Together they form a unique fingerprint.

  • Cite this