Document Detail


Degradation of islet amyloid polypeptide by neprilysin.
MedLine Citation:
PMID:  22898766     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS/HYPOTHESIS: A progressive loss of pancreatic beta cell function, a decrease in beta cell mass and accumulation of islet amyloid is characteristic of type 2 diabetes mellitus. The main constituent of islet amyloid is islet amyloid polypeptide (IAPP). In this study, we examined the ability of the peptidase neprilysin to cleave IAPP and prevent human IAPP-induced pancreatic beta cell toxicity.
METHODS: Neprilysin and a catalytically compromised neprilysin mutant were tested for their ability to inhibit human IAPP fibrillisation and human IAPP-induced pancreatic beta cell cytotoxicity. Degradation of human IAPP by neprilysin was followed by HPLC, and the degradation products were identified by MS.
RESULTS: Neprilysin prevented IAPP fibrillisation by cleaving IAPP at Arg(11)-Leu(12), Leu(12)-Ala(13), Asn(14)-Phe(15), Phe(15)-Leu(16), Asn(22)-Phe(23) and Ala(25)-Ile(26). It also appears to prevent human IAPP fibrillisation through a non-catalytic interaction. Neprilysin protected against beta cell cytotoxicity induced by exogenously added or endogenously produced human IAPP.
CONCLUSIONS/INTERPRETATION: The data presented support a potential therapeutic role for neprilysin in preventing type 2 diabetes mellitus. This study supports the hypothesis that extracellular human IAPP contributes to human IAPP-induced beta cell cytotoxicity. Whether human IAPP exerts its cytotoxic effect through a totally extracellular mechanism or through a cellular reuptake mechanism is unclear at this time.
Authors:
H Guan; K M Chow; R Shah; C J Rhodes; L B Hersh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-17
Journal Detail:
Title:  Diabetologia     Volume:  55     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-11     Completed Date:  2013-02-26     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  2989-98     Citation Subset:  IM    
Affiliation:
Department of Molecular and Cellular Biochemistry, University of Kentucky, B236 Biomedical Biological Sciences Research Building, 741 South Limestone Street, Lexington, KY 40536-0509, USA. hguan2@uky.edu
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Amyloid / metabolism
Amyloid beta-Protein Precursor / genetics,  metabolism*
Animals
Apoptosis / drug effects,  physiology*
Cell Line, Tumor
Diabetes Mellitus, Type 2 / metabolism*,  pathology
Enzyme Activation / physiology
Green Fluorescent Proteins / genetics
Humans
Insulin-Secreting Cells / drug effects,  enzymology*
Insulinoma
Molecular Sequence Data
Neprilysin / genetics,  metabolism*,  pharmacology
Pancreatic Neoplasms
Rats
Recombinant Proteins / genetics,  metabolism,  pharmacology
Substrate Specificity / physiology
Transfection
Grant Support
ID/Acronym/Agency:
P20RR020171/RR/NCRR NIH HHS; R01 DK050610/DK/NIDDK NIH HHS; R01DA02243/DA/NIDA NIH HHS; R01DK50610/DK/NIDDK NIH HHS; R56 DK050610/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid; 0/Amyloid beta-Protein Precursor; 0/Recombinant Proteins; 147336-22-9/Green Fluorescent Proteins; EC 3.4.24.11/Neprilysin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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