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: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
04 Aug 2017
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| 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 
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| 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 |
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| 245 | 1 | 0 | |a Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift |c 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 |
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| 520 | |a 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. | ||
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