Structural and Functional Evidence for Citicoline Binding and Modulation of 20S Proteasome Activity: Novel Insights into its Pro-Proteostatic Effect.

Structural and Functional Evidence for Citicoline Binding and Modulation of 20S Proteasome Activity: Novel Insights into its Pro-Proteostatic Effect. Biochem Pharmacol. 2020 Apr 13;:113977 Authors: Sbardella D, Coletta A, Tundo GR, Ahmed IMM, Bellia F, Oddon F, Manni G, Coletta M Abstract Citicoline or CDP-choline is a drug, made up by a cytidine 5'-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5'-diphosphate and choline, easily bypassing the blood-brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histotypes which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, this molecule finds a therapeutic application in different neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citic...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research

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