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Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift

In humans, low serum carnosinase (CN1) activity protects patients with type 2 diabetes from diabetic nephropathy. We now characterized the interaction of thiol-containing compounds with CN1 cysteine residue at position 102, which is important for CN1 activity. Reduced glutathione (GSH), N-acetylcyst...

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Hauptverfasser: Peters, Verena (VerfasserIn) , Schmitt, Claus P. (VerfasserIn) , Weigand, Tim (VerfasserIn) , Klingbeil, Kristina (VerfasserIn) , Thiel, Christian (VerfasserIn) , Berg, Antje van den (VerfasserIn) , Nawroth, Peter Paul (VerfasserIn) , Fleming, Thomas (VerfasserIn) , Wagner, Andreas H. (VerfasserIn) , Hecker, Markus (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 04 Aug 2017
In: Journal of enzyme inhibition and medicinal chemistry
Year: 2017, Jahrgang: 32, Heft: 1, Pages: 1102-1110
ISSN:1475-6374
DOI:10.1080/14756366.2017.1355793
Online-Zugang:Verlag, Volltext: http://dx.doi.org/10.1080/14756366.2017.1355793
Verlag, Volltext: https://doi.org/10.1080/14756366.2017.1355793
Volltext
Verfasserangaben:Verena Peters, Claus P. Schmitt, Tim Weigand, Kristina Klingbeil, Christian Thiel, Antje van den Berg, Vittorio Calabrese, Peter Nawroth, Thomas Fleming, Elisabete Forsberg, Andreas H. Wagner, Markus Hecker, & Giulio Vistoli
Beschreibung
Zusammenfassung:In humans, low serum carnosinase (CN1) activity protects patients with type 2 diabetes from diabetic nephropathy. We now characterized the interaction of thiol-containing compounds with CN1 cysteine residue at position 102, which is important for CN1 activity. Reduced glutathione (GSH), N-acetylcysteine and cysteine (3.2 ± 0.4, 2.0 ± 0.3, 1.6 ± 0.2 µmol/mg/h/mM; p < .05) lowered dose-dependently recombinant CN1 (rCN1) efficiency (5.2 ± 0.2 µmol/mg/h/mM) and normalized increased CN1 activity renal tissue samples of diabetic mice. Inhibition was allosteric. Substitution of rCN1 cysteine residues at position 102 (Mut1C102S) and 229 (Mut2C229S) revealed that only cysteine-102 is influenced by cysteinylation. Molecular dynamic simulation confirmed a conformational rearrangement of negatively charged residues surrounding the zinc ions causing a partial shift of the carnosine ammonium head and resulting in a less effective pose of the substrate within the catalytic cavity and decreased activity. Cysteine-compounds influence the dynamic behaviour of CN1 and therefore present a promising option for the treatment of diabetes.
Beschreibung:Gesehen am 01.08.2018
Beschreibung:Online Resource
ISSN:1475-6374
DOI:10.1080/14756366.2017.1355793

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