Description | Insulysin was identified nearly a century ago as an enzyme responsible for the degradation of insulin in cells, although the precise interactions between insulin and insulysin remain elusive. Human insulysin was cloned in 1988, and shown to be a 118 kDa protein that exists primarily as a homodimer, and perhaps also complexed with other molecules. The sequence is well conserved between humans, rats and mice, and the antibody recognizes these species. Insulysin is a metalloproteinase of the clan ME, family M16, which contains an active site HxxEH, a reversal of the canonical HExxH zinc binding motif. Considered a zinc metalloproteinase, the activity of insulysin can be blocked with EDTA or 1-10 phenanthroline. In addition to the active metalloproteinase domain, insulysin contains a second metalloproteinase site which is considered catalytically inactive, and is thought to assist in substrate binding. Insulysin is most closely related to the bacterial proteinase pitrilysin, (the human orthologue of which appears to be MPRP1) and the mammalian proteinsae nardilysin. Generally thought to be a cytoplasmic protein, insulysin has been isolated from many different tissues and cell lines, and can degrade intact insulin, insulin B chain, glucagon, denatured hemoglobin, alpha amyloid protein, TGF alpha and amylin. Recent work implicates insulysin in clearing beta amyloid plaques from the brain, and has generated much interest in Alzheimer?s disease research. ThepH optimum for insulysin is basic,pH 8.5, which also distinguishes it from other metalloproteinases. Insulin degrading enzyme (IDE) has a preferential affinity for insulin such that the presence of insulin will inhibit IDE mediated degradation of other substrates. IDE degrades a variety of other peptides including atrial natriuretic peptide and amylin. Subcellular location: Cytoplasm, Cell membrane, Extracellular matrix Target Information: This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]. |