Reactome | Insulin degradation

Insulin degradation

Stable Identifier

R-HSA-74730

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

endosome

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, Métioui, 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