The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase. Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis.
The enzyme 4-hydroxyphenylpyruvate dioxygenase 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. This study evaluated the inhibitory effect of 91 extracts on 4-hydroxyphenylpyruvate dioxygenase from mostly native plants from central Argentina. Flourensia oolepis ethanol extract showed itself to be the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 µM and a KI of 13.7 µM, behaved as a reversible inhibitor of the enzyme and as a noncompetitive 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, cocrystallized with 4-hydroxyphenylpyruvate dioxygenase. The main structural determinants that confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with 4-hydroxyphenylpyruvate dioxygenase revealed the basis of the noncompetitive reversible mechanism of inhibition at the 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 4-hydroxyphenylpyruvate dioxygenase inhibitors for the treatment of tyrosinemia type 1 and other disorders associated with tyrosinase catabolism.
Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina.
María Eugenia
ME
Chiari
Department of Chemistry, College of Exact and Natural Sciences, National University of Mar del Plata, Argentina.
Leonardo
L
Tosoni
Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina.
Mariana Belén
MB
Joray
Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina.
Georgina Natalia
GN
Diaz Napal
Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina.
Sara María
SM
Palacios
Herbarium Marcelino Sayago, School of Agricultural Science, Catholic University of Córdoba, Argentina.
Gustavo Miguel
GM
Ruiz
Department of Chemistry, College of Exact and Natural Sciences, National University of Mar del Plata, Argentina.
Domingo Mariano A
DM
Vera
Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina.
María Cecilia
MC
Carpinella
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001118:Argentina; D019659:Asteraceae / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D044950:Flavanones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013552:Swine
D004791:Enzyme Inhibitors; D044950:Flavanones; C016063:pinocembrin; D015111:4-Hydroxyphenylpyruvate Dioxygenase