The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenasee. Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis

MARÍA EUGENIA CHIARI; LEONARDO TOSONI; MARIANA BELÉN JORAY; GEORGINA NATALIA DIAZ NAPAL; SARA MARÍA PALACIOS; GUSTAVO MIGUEL RUIZ; DOMINGO MARIANO A. VERA *; MARÍA CECILIA CARPINELLA *

PLANTA MEDICA

GEORG THIEME VERLAG KG

Lugar: Berlin; Año: 2015 vol. 81 p. 1380 - 1391

0032-0943

p { margin-bottom: 0.21cm; direction: ltr; line-height: 120%; text-align: justify; }p.western { font-family: "Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "Times New Roman"; font-size: 12pt; }p.ctl { font-family: "Times New Roman"; font-size: 10pt; }a:link { color: rgb(0, 0, 255); }The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes thesecond step in the tyrosine degradation pathway. In mammals, thisenzyme is the molecular target of drugs used for the treatment ofmetabolic disorders associated with defects in the tyrosinecatabolism, mainly the fatal hereditary disease tyrosinemia type 1(TH1). This study evaluated the inhibitory effect on HPPD of 91, mostlynative, plants from central Argentina. Flourensia oolepisethanol extract showed itself the most effective, andbioguided fractionation yielded pinocembrin (1)as its active principle. This flavanone,with an IC50value of 73.1 Mand a KIof 13.7 M,behaved as a reversible inhibitor of theenzyme and as a non-competitiveinhibitor. Molecular modelingstudies confirmed the inhibitory potency of 1 and explainedits activity by means of in silico determination of itsbinding mode in comparison to inhibitors of known activity,co-crystallized with the HPPD. The main structural determinants whichconfer its potency are discussed. Analysis ofthe binding mode of theflavanone 1with HPPD revealed the basis of the non-competitive reversiblemechanism of inhibition at molecular level, which seems to be acommon characteristic in this ubiquitous family of natural compounds.The resulting information may establish the basis for obtaining novelHPPD inhibitors for treatment of TH1 and other disorders associatedwith tyrosinase catabolism.