Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation.
Insulin-degrading enzyme (IDE) is responsible for the degradation of a number of hormones and peptides, including insulin and amyloid beta (Abeta). 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 Abeta degrading activities of IDE. Insulin-degrading activity appeared more sensitive to NO inhibition than Abeta 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.
Cordes
Crystal M
CM
Research Service, Omaha Veterans Affairs Medical Center, Omaha, NE 68105, USA.
Bennett
Robert G
RG
Siford
Gerri L
GL
Hamel
Frederick G
FG
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D007328:Insulin; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D007339:Insulysin