Molecular insights into the binding of carnosine and anserine to human serum carnosinase 1 (CN1)

Abstract

Carnosine (CAR) and anserine (ANS) are histidine-containing dipeptides that show the therapeutic properties and protective abilities against diabetes and cognitive deficit. Both dipeptides are rich in meat products and have been used as a supplement. However, in humans, both compounds have a short half-life due to the rapid degradation by dizinc carnosinase 1 (CN1) which is a hurdle for its therapeutic application. To date, a comparative study of carnosine- and anserine-CN1 complexes is limited. Thus, in this work, molecular dynamics (MD) simulations were performed to explore the binding of carnosine and anserine to CN1. CN1 comprises 2 chains (Chains A and B). Both monomers are found to work independently and alternatingly. The displacement of Zn2+ pair is found to disrupt the substrate binding. CN1 employs residues from the neighbour chain (H235, T335, and T337) to form the active site. This highlights the importance of a dimer for enzymatic activity. Anserine is more resistant to CN 1 than carnosine because of its bulky and dehydrated imidazole moiety. Although both dipeptides can direct the peptide oxygen to the active Zn2+ which can facilitate the catalytic reaction, the bulky methylated imidazole on anserine promotes various poses that can retard the hydrolytic activity in contrast to carnosine. Anserine is likely to be the temporary competitive inhibitor by retarding the carnosine catabolism.