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The Trypanosoma cruzi ascorbate peroxidase is, by sequence analysis, a hybrid type A member of class I heme peroxidases [ Tc APx-cytochrome c peroxidase (CcP)], suggesting both ascorbate (Asc) and cytochrome c (Cc) peroxidase activity. Here, we show that the enzyme reacts fast with H 2 O 2 ( k = 2.9 × 10 7 M -1 ⋅s -1 ) and catalytically decomposes H 2 O 2 using Cc as the reducing substrate with higher efficiency than Asc ( k  cat / K  m = 2.1 × 10 5 versus 3.5 × 10 4 M -1 ⋅s -1 , respectively). Visible-absorption spectra of purified recombinant Tc APx-CcP after H 2 O 2 reaction denote the formation of a compound I-like product, characteristic of the generation of a tryptophanyl radical-cation (Trp 233•+ ). Mutation of Trp 233 to phenylalanine (W233F) completely abolishes the Cc-dependent peroxidase activity. In addition to Trp 233•+ , a Cys 222 -derived radical was identified by electron paramagnetic resonance spin trapping, immunospin trapping, and MS analysis after equimolar H 2 O 2 addition, supporting an alternative electron transfer (ET) pathway from the heme. Molecular dynamics studies revealed that ET between Trp 233 and Cys 222 is possible and likely to participate in the catalytic cycle. Recognizing the ability of Tc APx-CcP to use alternative reducing substrates, we searched for its subcellular localization in the infective parasite stages (intracellular amastigotes and extracellular trypomastigotes). Tc APx-CcP was found closely associated with mitochondrial membranes and, most interestingly, with the outer leaflet of the plasma membrane, suggesting a role at the host-parasite interface. Tc APx-CcP overexpressers were significantly more infective to macrophages and cardiomyocytes, as well as in the mouse model of Chagas disease, supporting the involvement of Tc APx-CcP in pathogen virulence as part of the parasite antioxidant armamentarium.

proceedings of the national academy of sciences of the united states of america

Kinetics, subcellular localization, and contribution to parasite virulence of a <i>Trypanosoma cruzi</i> hybrid type A heme peroxidase ( <i>Tc</i> APx-CcP)

Kinetics, subcellular localization, and contribution to parasite virulence of a Trypanosoma cruzi hybrid type A heme peroxidase ( Tc APx-CcP)