Insulin degradation

Stable Identifier
R-HSA-74730
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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IDE dimer in the endosome lumen catalyzes the processive degradation of insulin into multiple inactive fragments (Manolopoulou et al. 2009; Zhang et al. 2018) Insulin released into the endosome is rapidly degraded.

Two enzymes known to be present in liver parenchymal cells, insulin-degrading enzyme (IDE) and cathepsin D (CTSD) degrade insulin efficiently in vitro, and both are annotated as candidate catalysts of this reaction. The identity of the enzyme or enzymes mediating this degradation in vivo remains controversial, however. By a variety of immunological and enzymological criteria, catalytically active material from rat liver fractions exhibited properties distinct from those expected for insulin-degrading enzyme (IDE) (Authier et al. 1994), indistinguishable from those expected for cathepsin D (CTSD), and sufficient to account for the insulin-degrading activity in these fractions (Authier et al. 2002). Nevertheless, IDE deficiency in vivo is associated with abnormal insulin turnover, IDE is present at low levels in endosomes and biochemical studies indicate that IDE efficiently degrades insulin (Shen et al. 2006; Manopoulou et al. 2009; Zhang et al. 2018).

The active form of IDE is a dimer with one Zn++ bound to each protein subunit (Li et al. 2006).

Literature References
PubMed ID Title Journal Year
8300632 Endosomal proteolysis of insulin by an acidic thiol metalloprotease unrelated to insulin degrading enzyme

Posner, BI, Bergeron, JJ, Rachubinski, RA, Authier, F

J Biol Chem 1994
11779865 Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D

Fabrega, S, M├ętioui, M, Authier, F, Briand, G, Kouach, M

J Biol Chem 2002
16574064 The C-terminal domain of human insulin degrading enzyme is required for dimerization and substrate recognition

Tang, WJ, Kuo, WL, Rosner, MR, Li, P, Yousef, M

Biochem Biophys Res Commun 2006
19321446 Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme

Manolopoulou, M, Tang, WJ, Schilling, AB, Guo, Q, Malito, E

J Biol Chem 2009
17051221 Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

Tang, WJ, Rosner, MR, Joachimiak, A, Shen, Y

Nature 2006
29596046 Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme

Wang, A, Koide, S, McCord, LA, Tang, WJ, Carragher, B, Woods, VA, Tan, YZ, Wei, H, Li, S, Liang, WG, Potter, CS, Lee, D, Koide, A, Kossiakoff, AA, Deprez-Poulain, R, Zhang, Z, Bailey, LJ, Shang, W, Farcasanu, M, Deprez, B, Liu, DR

Elife 2018
Participants
Participates
Catalyst Activity

endopeptidase activity of IDE, CTSD [endosome lumen]

Orthologous Events
Created
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