Identification of conoidin A as a covalent inhibitor of peroxiredoxin II

Jeralyn D. Haraldsen; Gu Liu; Catherine H. Botting; Jeffrey G. A. Walton; Janet Storm; Timothy J. Phalen; Lai Yu Kwok; Dominique Soldati-Favre; Nicholas H. Heintz; Sylke Müller; Nicholas J. Westwood; Gary E. Ward

doi:10.1039/B901735F

Identification of conoidin A as a covalent inhibitor of peroxiredoxin II†

Jeralyn D. Haraldsen,‡^a Gu Liu,‡^b Catherine H. Botting,^b Jeffrey G. A. Walton,^b Janet Storm,^c Timothy J. Phalen,^d Lai Yu Kwok,^e Dominique Soldati-Favre,^e Nicholas H. Heintz,^d Sylke Müller,^c Nicholas J. Westwood*^b and Gary E. Ward*^a

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* Corresponding authors

^a Department of Microbiology and Molecular Genetics, 316 Stafford Hall, University of Vermont, 95 Carrigan Drive, Burlington, VT, USA
E-mail: Gary Ward@uvm.edu
Fax: 802-656-8749

^b School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, Scotland, UK
E-mail: njw3@st-andrews.ac.uk
Fax: 44-1-334-462595

^c Institute of Biomedical and Life Sciences, Infection and Immunity, Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, Scotland, UK

^d Department of Pathology, HSRF 328, University of Vermont, Burlington, VT, USA

^e Department of Microbiology and Molecular Medicine, Faculty of Medicine - University of Geneva, CMU, 1 rue Michel-Servet, Geneva 4, Switzerland

Abstract

Conoidin A (1) is an inhibitor of host cell invasion by the protozoan parasite Toxoplasma gondii. In the course of studies aimed at identifying potential targets of this compound, we determined that it binds to the T. gondii enzyme peroxiredoxin II (TgPrxII). Peroxiredoxins are a widely conserved family of enzymes that function in antioxidant defense and signal transduction, and changes in PrxII expression are associated with a variety of human diseases, including cancer. Disruption of the TgPrxII gene by homologous recombination had no effect on the sensitivity of the parasites to 1, suggesting that TgPrxII is not the invasion-relevant target of 1. However, we showed that 1 binds covalently to the peroxidatic cysteine of TgPrxII, inhibiting its enzymatic activity in vitro. Studies with human epithelial cells showed that 1 also inhibits hyperoxidation of human PrxII. These data identify Conoidin A as a novel inhibitor of this important class of antioxidant and redox signaling enzymes.

Organic & Biomolecular Chemistry

Identification of conoidin A as a covalent inhibitor of peroxiredoxin II†

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Identification of conoidin A as a covalent inhibitor of peroxiredoxin II

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