ABSTRACT
The insulin degrading enzyme (IDE; insulysin; EC 3.4.24.56) is the initial representative of a proposed new superclass of metalloproteinases. IDE is sensitive to chelating agents and contains tightly-bound Zn2 + but does not have the typical Zn2 + binding motif of classical zinc metalloproteinases. Other members of this proposed new superclass include proteinases in Escherichia coli (Protease III; pitrilysin; EC 3.4.24.55) and Drosophila (growth factor binding and degrading enzyme), both of which are homologous with mammalian IDE, and several mitochondrial enzymes. IDE is a 110000 MW protein with a neutral pH optimum, sulphydryl dependence, and a very high affinity for insulin. It also binds and degrades a variety of other growth-related hormones and glucagon, and may have activity toward unrelated peptides and proteins. The enzyme recognizes three-dimensional structure characteristics of its substrates rather than specific peptide bonds. In cells, IDE has been found in all cell types examined, with a primary localization to the cytosol. The enzyme can also be found in endosomes, peroxisomes and on the plasma membrane. IDE has been shown to exist in complexes with other proteins, notably some steroid receptors and the multicatalytic proteinase. It has been implicated in the physiological process of cellular insulin degradation in the endosome and has been suggested as important in cellular growth and development, perhaps by interaction with growth factors. IDE has been suggested to play a role in insulin action and to be a potential factor in certain clinical states of insulin resistance. The actual role of this enzyme in both normal and pathological states remains uncertain.
