title: Epigallocatechin-3-gallate potently inhibits the in vitro activity of hydroxy-3-methyl-glutaryl-CoA reductase.
abstract: Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) is the rate-controlling enzyme of cholesterol synthesis, and owing to its biological and pharmacological relevance, researchers have investigated several compounds capable of modulating its activity with the hope of developing new hypocholesterolemic drugs. In particular, polyphenol-rich extracts were extensively tested for their cholesterol-lowering effect as alternatives, or adjuvants, to the conventional statin therapies, but a full understanding of the mechanism of their action has yet to be reached. Our work reports on a detailed kinetic and equilibrium study on the modulation of HMGR by the most-abundant catechin in green tea, epigallocatechin-3-gallate (EGCG). Using a concerted approach involving spectrophotometric, optical biosensor, and chromatographic analyses, molecular docking, and site-directed mutagenesis on the cofactor site of HMGR, we have demonstrated that EGCG potently inhibits the in vitro activity of HMGR (K(i) in the nanomolar range) by competitively binding to the cofactor site of the reductase. Finally, we evaluated the effect of combined EGCG-statin administration.
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Camerino, Italy. massimiliano.cuccioloni@unicam.it
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.forename: Matteo
authors.initials: M
authors.lastname: Mozzicafreddo
authors.forename: Michele
authors.initials: M
authors.lastname: Spina
authors.forename: Chi Nhan
authors.initials: CN
authors.lastname: Tran
authors.forename: Maurizio
authors.initials: M
authors.lastname: Falconi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Eleuteri
authors.forename: Mauro
authors.initials: M
authors.lastname: Angeletti
mesh_terms: D015374:Biosensing Techniques; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019295:Computational Biology; D004789:Enzyme Activation / Q000187:drug effects; D057075:Enzyme Assays; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011994:Recombinant Proteins; D002392:Catechin; C045651:epigallocatechin gallate; D006903:Hydroxymethylglutaryl CoA Reductases