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

作者：Peters Verena^*; Schmitt Claus P; Weigand Tim; Klingbeil Kristina; Thiel Christian; van den Berg Antje; Calabrese Vittorio; Nawroth Peter; Fleming Thomas; For**erg Elisabete; Wagner Andreas H; Hecker Markus; Vistoli Giulio

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, 32(1): 1102-1110.

DOI：10.1080/14756366.2017.1355793

• Carnosinase 1 activity
• CN1
• allosteric inhibition
• glutathione
• N-acetylcysteine
• diabetes

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 mu mol/mg/h/mM; p < .05) lowered dose-dependently recombinant CN1 (rCN1) efficiency (5.2 +/- 0.2 mu mol/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 (Mut1(C102S)) and 229 (Mut2(C229S)) 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.

• 出版日期2017