Carnosine and Homocarnosine Degradation Mechanisms by the Human Carnosinase Enzyme CN1: Insights from Multiscale Simulations.

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 Zn(2+) ions, bridged by a hydroxide anion.

Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein.

Prion diseases are fatal neurodegenerative disorders in mammals and other animal species. In humans, about 15% of these maladies are caused by pathogenic mutations (PMs) in the gene encoding for the prion protein (PrP(C)). Seven PMs are located in the naturally unfolded PrP(C) N-terminal domain, which constitutes about half of the protein.

Computational studies on the prion protein.

Prion diseases are rare neurodegenerative diseases characterized by the conversion of the prion protein from its native state (PrP(C)) towards the so-called 'scrapie form', rich in β-strands. Computational approaches, here briefly reviewed, are instrumental to understand the intrinsic instability of PrP(C) fold and how the latter is affected by mutations, binding of metals as well as by different environmental conditions, such as pH and temperature. These studies also provide a structural basis for the binding of anti-prion compounds, which may block the conversion to the scrapie form and, consequently, may inhibit fibril formation.