Abstract
The inhibition of recombinant CpLIP2 lipase/acyltransferase from Candida parapsiolosis was considered a key model for novel antifungal drug discovery and a potential therapeutic target for candidiasis. Lipases have identified recently as potent virulence factors in C. parapsilosis and some other yeasts. The inhibition effects of orlistat and four flavonols (galangin, kaempferol, quercetin and myricetin) characterized by an increasing degree of hydroxylation in B-ring, were investigated using ethyl oleate hydrolysis as the model reaction. Orlistat and kaempferol (14 µM) strongly inhibited CpLIP2 catalytic activity within 1 min of pre-incubation, by 90% and 80%, respectively. The relative potency of flavonols as inhibitors was: kaempferol > quercetin > myricetin > galangin. The results suggested that orlistat bound to the catalytic site while kaempferol interacted with W294 on the protein lid. A static mechanism of interactions between flavonols and CpLIP2 lipase was confirmed by fluorescence quenching analyses, indicating that the interactions were mainly driven by hydrophobic bonds and electrostatic forces. From the Lehrer equation, fractions of tryptophan accessibility to the quencher were evaluated, and a relationship with the calculated number of binding sites was suggested.
Highlights
Flavonoids are a subgroup of phenolics belonging to plant secondary metabolites
A strong inhibition of the hydrolysis activity of CpLIP2 was observed after only 1 min of prepre-incubation for all THL concentrations compared to the control
The inhibitory effect provided by THL on the hydrolytic activity of CpLIP2 lipase was faster and stronger relative to the effect of KAE, itself showing the highest inhibition among the four flavonols tested
Summary
Flavonoids are a subgroup of phenolics belonging to plant secondary metabolites. They are classified in several subclasses including chalcones, flavanones, flavonols, flavones, isoflavones, flavan-3-ols, flavan 3-4 diols, anthocyanidins and aurones, each varying in their chemical structures and properties [1]. Flavonoids are bioactive compounds having therapeutic and preventive effects [8] through antioxidant, anti-inflammatory, anti-mutagenic, anti-carcinogenic [9], antibacterial and antifungal activities [10,11]. A strong relationship between the degree of hydroxylation of flavonoid structures and their fungicidal activities has been reported [12].
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