Document Detail

Synergistic inhibition of the enzymatic activity of aminopeptidase N by divalent metal ion chelators.
MedLine Citation:
PMID:  17109655     Owner:  NLM     Status:  MEDLINE    
Membranes of HEK293 cells that were transfected with human aminopeptidase N (AP-N, CD13, EC and purified soluble porcine kidney AP-N were used to study inhibition of its enzyme activity by divalent cation chelators. Whereas pre-incubation for 10 min with ethylenediaminetetraacetic acid (EDTA), did not or only weakly affected the enzyme activity, the bidentate chelator 1,10-phenanthroline produced a complete and concentration-dependent inhibition of AP-N. The corresponding curves had Hill slopes of 2.50 +/- 0.23 and 2.73 +/- 0.01 for soluble and recombinant AP-N respectively. EDTA increased the potency of 1,10-phenanthroline till a limit, at which Hill slopes became close to unity. In the absence of EDTA, the inhibition by 1,10-phenanthroline was only weakly affected by the substrate concentration. On the other hand, competition between 1,10-phenanthroline and the substrate took place in the presence of EDTA. Similar findings were reported for the related metallopeptidase cystinyl aminopeptidase and point towards a model in which 1,10-phenanthroline inhibit enzyme activity by decreasing the free Zn2+ concentration. Moreover, EDTA is capable of removing a modulatory ion from an allosteric site at the enzyme, facilitating the direct interaction between 1,10-phenanthroline and the catalytic Zn2+. Compatible with this model, Ca2+ may bind to this allosteric site resulting in the potentiation of Zn2+-mediated re-activation of the enzyme activity in the presence of EDTA and 1,10-phenanthroline.
Patrick M L Vanderheyden; Heidi Demaegdt; Julie Swales; Pieter-Jan Lenaerts; Jean-Paul De Backer; Lotte K Vogel; Georges Vauquelin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Fundamental & clinical pharmacology     Volume:  20     ISSN:  0767-3981     ISO Abbreviation:  Fundam Clin Pharmacol     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-19     Completed Date:  2007-03-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8710411     Medline TA:  Fundam Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  613-9     Citation Subset:  IM    
Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
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MeSH Terms
Antigens, CD13 / antagonists & inhibitors*,  metabolism
Cations, Divalent / metabolism*,  pharmacology
Cells, Cultured
Chelating Agents / metabolism,  pharmacology*
Dose-Response Relationship, Drug
Drug Synergism
Edetic Acid / pharmacology
Phenanthrolines / pharmacology
Recombinant Proteins / metabolism
Zinc / pharmacology
Reg. No./Substance:
0/Cations, Divalent; 0/Chelating Agents; 0/Phenanthrolines; 0/Recombinant Proteins; 60-00-4/Edetic Acid; 66-71-7/1,10-phenanthroline; 7440-66-6/Zinc; EC, CD13

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