Morelloflavone from Garcinia dulcis as a novel biflavonoid inhibitor of HMG-CoA reductase.
Morelloflavone, a biflavonoid from Garcinia dulcis previously shown to have hypocholesterolemic activity, was examined for its effect on HMG-CoA reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway. By using the catalytic domain of house mouse HMG-CoA reductase, morelloflavone was found to inhibit the enzyme activity by competing with HMG-CoA whereas it was non-competitive towards NADPH. The inhibition constants (K(i)) with respect to HMG-CoA and NADPH were 80.87 ± 0.06 µm and 103 ± 0.07 µm, respectively. Both flavonoid subunits of this compound, naringenin and luteolin, equally competed with HMG-CoA with K(i) of 83.58 ± 4.37 µm and 83.59 ± 0.94 µm, respectively, and were also non-competitive with NADPH (K(i) of 182 ± 0.67 µm and 188 ± 0.14 µm, respectively). Due to these findings, we suggest that each subunit of morelloflavone would occupy the active site of the enzyme, thereby blocking access of its substrate. The present study thus demonstrates the ability of morelloflavone from G. dulcis to inhibit HMG-CoA reductase in vitro. As a result, this biflavonoid might serve as a new candidate for the future development of hypocholesterolemic agents.
Tuansulong
Ku-Aida
KA
Department of Biochemistry, Faculty of Science, Prince of Songkla University, Hat-Yai, Thailand.
Hutadilok-Towatana
Nongporn
N
Mahabusarakam
Wilawan
W
Pinkaew
Decha
D
Fujise
Ken
K
D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology; D029760:Garcinia / Q000737:chemistry*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047311:Luteolin / Q000494:pharmacology; D051379:Mice; D009249:NADP / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D044946:Biflavonoids; D044950:Flavanones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011994:Recombinant Proteins; C105620:morelloflavone; D009249:NADP; D006903:Hydroxymethylglutaryl CoA Reductases; C005273:naringenin; D047311:Luteolin