The inhibitory activity of plants from central Argentina on p-hydroxyphenylpyruvate dioxygenase. Isolation and mechanism of inhibition of a flavanone from Flourensia oolepis

CHIARI M.E.; TOSONI L.; JORAY M.B.; DIAZ NAPAL, G.N.; PALACIOS S. M.; RUIZ G. M.; VERA D.M.A.; CARPINELLA M. C.

PLANTA MEDICA

GEORG THIEME VERLAG KG

Año: 2015 vol. 81 p. 1382 - 1391

0032-0943

The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the second step in the tyrosine degradation pathway. In mammals, this enzyme is the molecular target of drugs used for the treatment of metabolic disorders associated with defects in the tyrosine catabolism, mainly the fatal hereditary disease tyrosinemia type 1 (TH1). This study evaluated the inhibitory effect on HPPD of 91, mostly native, plants from central Argentina. Flourensia oolepis ethanol extract showed itself the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 M and a KI of 13.7 M, behaved as a reversible inhibitor of the enzyme and as a non-competitive inhibitor. Molecular modeling studies confirmed the inhibitory potency of 1 and explained its activity by means of in silico determination of its binding mode in comparison to inhibitors of known activity, co-crystallized with the HPPD. The main structural determinants which confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with HPPD revealed the basis of the non-competitive reversible mechanism of inhibition at molecular level, which seems to be a common feature in this ubiquitous family of natural compounds. The resulting information may establish the basis for obtaining novel HPPD inhibitors for treatment of TH1 and other disorders associated with tyrosinase catabolism.