Artículo
Crystal structure of Trypanosoma cruzi heme peroxidase and characterization of its substrate specificity and compound I intermediate
Freeman, Samuel L.; Skafar, Vera; Kwon, Hanna; Fielding, Alistair J.; Moody, Peter C.E.; Martínez, Alejandra; Issoglio, Federico Matías
; Inchausti, Lucas; Smircich, Pablo; Zeida, Ari; Piacenza, Lucía; Radi, Rafael; Raven, Emma L.
Fecha de publicación:
08/2022
Editorial:
American Society for Biochemistry and Molecular Biology
Revista:
Journal of Biological Chemistry (online)
ISSN:
0021-9258
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
The protozoan parasite Trypanosoma cruzi is the causative agent of American trypanosomiasis, otherwise known as Chagas disease. To survive in the host, the T. cruzi parasite needs antioxidant defense systems. One of these is a hybrid heme peroxidase, the T. cruzi ascorbate peroxidase-cytochrome c peroxidase enzyme (TcAPx-CcP). TcAPx-CcP has high sequence identity to members of the class I peroxidase family, notably ascorbate peroxidase (APX) and cytochrome c peroxidase (CcP), as well as a mitochondrial peroxidase from Leishmania major (LmP). The aim of this work was to solve the structure and examine the reactivity of the TcAPx-CcP enzyme. Low temperature electron paramagnetic resonance spectra support the formation of an exchange-coupled [Fe(IV)=O Trp233•+] compound I radical species, analogous to that used in CcP and LmP. We demonstrate that TcAPx-CcP is similar in overall structure to APX and CcP, but there are differences in the substrate-binding regions. Furthermore, the electron transfer pathway from cytochrome c to the heme in CcP and LmP is preserved in the TcAPx-CcP structure. Integration of steady state kinetic experiments, molecular dynamic simulations, and bioinformatic analyses indicates that TcAPx-CcP preferentially oxidizes cytochrome c but is still competent for oxidization of ascorbate. The results reveal that TcAPx-CcP is a credible cytochrome c peroxidase, which can also bind and use ascorbate in host cells, where concentrations are in the millimolar range. Thus, kinetically and functionally TcAPx-CcP can be considered a hybrid peroxidase.
Palabras clave:
ASCORBATE
,
CHAGAS DISEASE
,
CYTOCHROME C
,
HEME
,
OXIDANTS
,
PEROXIDASE
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Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Citación
Freeman, Samuel L.; Skafar, Vera; Kwon, Hanna; Fielding, Alistair J.; Moody, Peter C.E.; et al.; Crystal structure of Trypanosoma cruzi heme peroxidase and characterization of its substrate specificity and compound I intermediate; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 298; 8; 8-2022; 1-10
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