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Planta Med 2015; 81(15): 1382-1391
DOI: 10.1055/s-0035-1557864
Biological Screening
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

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

María Eugenia Chiari
1   Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina
,
Leonardo Tosoni
2   Department of Chemistry, College of Exact and Natural Sciences, National University of Mar del Plata, Argentina
,
Mariana Belén Joray
1   Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina
,
Georgina Natalia Diaz Napal
1   Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina
,
Sara María Palacios
1   Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina
,
Gustavo Miguel Ruiz
3   Herbarium Marcelino Sayago, School of Agricultural Science, Catholic University of Córdoba, Argentina
,
Domingo Mariano A. Vera
2   Department of Chemistry, College of Exact and Natural Sciences, National University of Mar del Plata, Argentina
,
María Cecilia Carpinella
1   Fine Chemical and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Argentina
› Author Affiliations
Further Information

Publication History

received 09 December 2014
revised 01 April 2015

accepted 14 June 2015

Publication Date:
20 August 2015 (online)

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Abstract

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.

Key words

Flourensia oolepis - Asteraceae - HPPD inhibitors - Argentinian native plants - pinocembrin - molecular docking

Supporting Information

 

  • References

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