Crystal structure of Trypanosoma cruzi heme peroxidase and characterization of its substrate specificity and compound I intermediate

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.Fil: Freeman, Samuel L.. University of Bristol; Reino UnidoFil: Skafar, Vera. Universidad de la República; UruguayFil: Kwon, Hanna. University of Leicester; Reino UnidoFil: Fielding, Alistair J.. Liverpool John Moores University; Reino UnidoFil: Moody, Peter C.E.. University of Leicester; Reino UnidoFil: Martínez, Alejandra. Universidad de la República; UruguayFil: Issoglio, Federico Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidade Nova de Lisboa; PortugalFil: Inchausti, Lucas. Universidad de la Republica; Uruguay. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Smircich, Pablo. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay. Universidad de la Republica; UruguayFil: Zeida, Ari. Universidad de la Republica; UruguayFil: Piacenza, Lucía. Universidad de la Republica; UruguayFil: Radi, Rafael. Universidad de la Republica; UruguayFil: Raven, Emma L.. University of Bristol; Reino Unid

Psychosis and Substance Abuse increase the COVID-19 mortality risk

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been a global challenge. High mortality rates have been reported in some risk groups, including patients with pre-existing mental disorders. METHODS: We used electronic health records to retrospectively identify people infected due to COVID-19 (between March 2020 and March 2021) in the three territories of the Basque Country. COVID-19 cases were defined as individuals who had tested positive on a reverse transcription-polymerase chain reaction (PCR) test. Univariate and multivariate logistic regression models and multilevel analyses with generalized estimated equations were used to determine factors associated with COVID-19-related mortality and hospital admission. RESULTS: The COVID-19 mortality rate was increased for patients with psychotic disorders [odds ratio (OR) adjusted: 1.45, 95% confidence interval (CI) (1.09–1.94), p = 0.0114] and patients with substance abuse [OR adjusted: 1.88, 95% CI (1.13–3.14, p < 0.0152)]. The mortality rate was lower for patients with affective disorders [OR adjusted: 0.80, 95% CI (0.61–0.99), p = 0.0407]. Hospital admission rates due to COVID-19 were higher in psychosis [OR adjusted: 2.90, 95% CI (2.36–3.56), p < 0.0001] and anxiety disorder groups [OR adjusted: 1.54, 95% CI (1.37–1.72), p < 0.0001]. Among admitted patients, COVID-19 mortality rate was decreased for those with affective disorders rate [OR adjusted: 0.72, 95% CI (0.55–0.95), p = 0.0194]. CONCLUSIONS: COVID-19-related mortality and hospitalizations rates were higher for patients with a pre-existing psychotic disorder