عنوان
پدید آورنده
موضوع
رده
کتابخانه
محل استقرار
TLpq2439583742
انگلیسی
Kinetic Effects of Mutations in IDE's Exosite on the Degradation of Insulin and Glucagon
[Thesis]
Islam, Saadman
Lazo, Noel D.
Clark University
2020
269
M.S.C.
Clark University
2020
Insulin-degrading enzyme (IDE) is a ubiquitous metalloprotease that degrades multiple substrates. As its name implies, IDE proteolyzes insulin, a hormone that facilitates glucose metabolism. However, IDE also proteolyzes glucagon, a hormone that opposes the effect of insulin by increasing glucose levels. IDE inhibitors for the treatment of type-2 diabetes mellitus (T2DM), thus, should be substrate-selective such that the IDE-dependent degradation of insulin is inhibited with little or no effect on glucagon degradation. It is hypothesized here that the development of these inhibitors depend on the elucidation of the mechanism IDE uses to recognize and bind its substrates prior to catalysis. Moreover, it is hypothesized that electrostatic interactions involving Glu341, a negatively charged residue in IDE's exosite play a key role in substrate binding. To test this hypothesis, two mutations, E341A and E341K, which change Glu341 to a neutral and positively charged residue, respectively, were studied. Kinetic studies based on the α-helical circular dichroic signal of insulin show that the E341A and E341K mutations enhance the degradation of insulin. In contrast, kinetic studies using liquid chromatography reveal that the E341A and E341K mutations inhibit the degradation of glucagon. Together, these findings show that Glu341 is a key residue in substrate binding and that modulation of electrostatic interactions between IDE's exosite and its substrates is an attractive strategy for moderating IDE's activity in a substrate-selective manner.
Biochemistry
Biology
Biophysics
Islam, Saadman
Lazo, Noel D.
مطالعه متن کتاب p
[Thesis]
276903
a
Y
