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| Home > Publications database > Carnosine and Homocarnosine Degradation Mechanisms by the Human Carnosinase Enzyme CN1: Insights from Multiscale Simulations > print |
| Home > Publications database > Carnosine and Homocarnosine Degradation Mechanisms by the Human Carnosinase Enzyme CN1: Insights from Multiscale Simulations > print |
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| 245 | _ | _ | |a Carnosine and Homocarnosine Degradation Mechanisms by the Human Carnosinase Enzyme CN1: Insights from Multiscale Simulations |
| 260 | _ | _ | |a Columbus, Ohio |c 2016 |b American Chemical Society |
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| 520 | _ | _ | |a The endogenous dipeptide l-carnosine, and its derivative homocarnosine, prevent and reduce several pathologies like amytrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease. Their beneficial action is severely hampered because of the hydrolysis by carnosinase enzymes, in particular the human carnosinase, hCN1. This belongs to the metallopeptidase M20 family, where a cocatalytic active site is formed by two Zn2+ ions, bridged by a hydroxide anion. The protein may exist as a monomer and as a dimer in vivo. Here we used hybrid quantum mechanics/molecular mechanics simulations based on the dimeric apoenzyme’s structural information to predict the Michaelis complexes with l-carnosine and its derivative homocarnosine. On the basis of our calculations, we suggest that (i) l-carnosine degradation occurs through a nucleophilic attack of a Zn2+-coordinated bridging moiety for both monomer and dimer. This mechanistic hypothesis for hCN1 catalysis differs from previous proposals, while it is in agreement with available experimental data. (ii) The experimentally measured higher affinity of homocarnosine for the enzyme relative to l-carnosine might be explained, at least in part, by more extensive interactions inside the monomeric and dimeric hCN1’s active site. (iii) Hydrogen bonds at the binding site, present in the dimer but absent in the monomer, might play a role in the experimentally observed higher activity of the dimeric form. Investigations of the enzymatic reaction are required to establish or disprove this hypothesis. Our results may serve as a basis for the design of potent hCN1 inhibitors. |
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| 700 | 1 | _ | |a Rossetti, Giulia |0 P:(DE-Juel1)145921 |b 1 |e Corresponding author |
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| 773 | _ | _ | |a 10.1021/acs.biochem.5b01263 |g Vol. 55, no. 19, p. 2772 - 2784 |0 PERI:(DE-600)1472258-6 |n 19 |p 2772 - 2784 |t Biochemistry |v 55 |y 2016 |x 1520-4995 |
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