Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) is the rate-controlling enzyme of cholesterol synthesis, and due to its biological and pharmacological relevance, researchers 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). According to a concerted approach involving spectrophotometric, optical biosensor, and chromatographic analyses, molecular docking and site-directed mutagenesis on the cofactor site of HMGR, we demonstrated that EGCG potently inhibits the in vitro activity of HMGR (Ki in the nanomolar range), by competitively binding to the cofactor site of the reductase. Finally, we evaluated the effect of combined EGCG-statin administration.

Epigallocatechin-3-gallate potently inhibits the in vitro activity of hydroxy-3-methyl-glutaryl-CoA reductase.

CUCCIOLONI, Massimiliano;MOZZICAFREDDO, MATTEO;FALCONI, Maurizio;ELEUTERI, Anna Maria;ANGELETTI, Mauro
2011-01-01

Abstract

Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) is the rate-controlling enzyme of cholesterol synthesis, and due to its biological and pharmacological relevance, researchers 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). According to a concerted approach involving spectrophotometric, optical biosensor, and chromatographic analyses, molecular docking and site-directed mutagenesis on the cofactor site of HMGR, we demonstrated that EGCG potently inhibits the in vitro activity of HMGR (Ki in the nanomolar range), by competitively binding to the cofactor site of the reductase. Finally, we evaluated the effect of combined EGCG-statin administration.
2011
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/204231
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 22
  • Scopus 77
  • ???jsp.display-item.citation.isi??? 68
social impact