The major cysteine proteinase (cruzipain) from Trypanosoma cruzi is encoded by multiple polymorphic tandemly organized genes located on different chromosomes

Campetella, Oscar; Henriksson, Jan; Åslund, U.; Frasch, Alberto C.C.; Pettersson, Ulf; Cazzulo, Juan J.

doi:10.1016/0166-6851(92)90219-a

Cited by 167 publications

(102 citation statements)

References 20 publications

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“…Several pathogenic protozoan parasites, including Entamoeba histolytica (5), Leishmania (6 -8), Trypanosoma cruzi (9,10), Trypanosoma congolense (11), and Trypanosoma brucei (12), express multiple CP enzymes (reviewed in Ref. 13).…”

Section: Eishmania Mexicana Like Other New World Leishmaniamentioning

confidence: 99%

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Buxbaum

Denise

Coombs

et al. 2003

The Journal of Immunology

107

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C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Δcpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Δcpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Δcpb-infected IL-12p40−/− and STAT4−/− mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-γ response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.

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Section: Eishmania Mexicana Like Other New World Leishmaniamentioning

confidence: 99%

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Buxbaum

Denise

Coombs

et al. 2003

The Journal of Immunology

107

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“…9,10 This protease is expressed in all life cycle stages of the parasite and is involved in nutrition and fight against host defense mechanisms. [11][12][13][14] Addition of a cruzain inhibitor to cultures of mammalian cells exposed to trypomastigotes or to mammalian cells already infected with T. cruzi amastigotes blocks replication and differentiation of the parasite, thus interrupting the parasite life cycle. [15][16][17][18][19][20][21] Several groups have demonstrated that irreversible inhibition of cruzain by small molecules eradicates infection of the parasite in cell culture and animal models.…”

Section: Introductionmentioning

confidence: 99%

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

2015

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Cruzain is a primary cysteine protease expressed by the protozoan parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development of inhibitors of this protein is a promising target for designing an effective therapy against the disease. In this paper, the mechanism of inhibition of cruzain by two different irreversible peptidyl halomethyl ketones (PHK) inhibitors has been studied by means of hybrid quantum mechanics/molecular mechanics−molecular dynamics (MD) simulations to obtain a complete representation of the possible free energy reaction paths. These have been traced on free energy surfaces in terms of the potential of mean force computed at AM1d/MM and DFT/MM levels of theory. An analysis of the possible reaction mechanisms of the inhibition process has been performed showing that the nucleophilic attack of an active site cysteine, Cys25, on a carbon atom of the inhibitor and the cleavage of the halogen−carbon bond take place in a single step. PClK appears to be much more favorable than PFK from a kinetic point of view. This result would be in agreement with experimental studies in other papain-like enzymes. A deeper analysis of the results suggests that the origin of the differences between PClK and PFK can be the different stabilizing interactions established between the inhibitors and the residues of the active site of the protein. Any attempt to explore the viability of the inhibition process through a stepwise mechanism involving the formation of a thiohemiketal intermediate and a three-membered sulfonium intermediate has been unsuccessful. Nevertheless, a mechanism through a protonated thiohemiketal, with participation of His159 as a proton donor, appears to be feasible despite showing higher free energy barriers. Our results suggest that PClK can be used as a starting point to develop a proper inhibitor of cruzain.

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“…La cruzipaína pertenece a la familia de las cisteín proteinasas, y es codificada por un alto número de genes organizados como grupos localizados en diferentes cromosomas (23,24). Por tener un elevado número de copias se ha encontrado una variabilidad que va desde la ausencia de diferencias entre las copias (25) hasta formas muy divergentes, como es el caso de la cruzipaína 2 Trypanosoma cruzi, el flagelado que causa la enfermedad de Chagas, realiza su ciclo de vida entre reservorios mamíferos e insectos de la familia Reduviidae.…”

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Análisis de polimorfismos en los genes tripanotión reductasa y cruzipaína en cepas colombianas de Trypanosoma cruzi

et al. 2007

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Introducción. Los estudios genéticos en Trypanosoma cruzi han buscado establecer asociaciones de variantes genéticas del parásito con manifestaciones clínicas de la enfermedad, origen biológico y geográfico de los aislamientos; sin embargo, los resultados de asociación con los marcadores comúnmente usados en estos estudios han generado mucha controversia, principalmente en la asociación de grupos con características clínicas y epidemiológicas de la enfermedad. Objetivo. Se planteó determinar la variabilidad de genes que codifican para las proteínas tripanotión reductasa y cruzipaína, involucradas en mecanismos de infección y supervivencia del parásito en el hospedador mamífero, y probar la asociación de variantes génicas con origen biológico y geográfico de cepas colombianas de T. cruzi. Materiales y métodos. Se tipificaron por reacción en cadena de la polimerasa-polimorfismo de longitud del fragmento de restricción seis SNPs (Single Nucleotide Polymorphisms) en tripanotión reductasa y ocho SNPs en cruzipaína en 36 cepas colombianas de T. cruzi de diferentes regiones y origen biológico. Resultados. Con las enzimas Acy I y Hae III se determinaron tres genotipos para tripanotión reductasa. Para cruzipaína se identificaron seis genotipos con las enzimas Rsa I, Ban I y Bsu 36I. Conclusiones. Para tripanotión reductasa no fue posible establecer una asociación con el origen biológico o geográfico; sin embargo los alelos producidos en las posiciones 102 y 210, permitieron discriminar los grupos tradicionales I y II. Con los genotipos obtenidos para cruzipaína se establecieron relaciones a estos grupos, origen biológico y geográfico. Los resultados sugieren la utilidad de estos genes como marcadores moleculares para determinar y diferenciar variedades genéticas en T. cruzi.Palabras clave: Trypanosoma cruzi, genes protozoarios, polimorfismo, polimorfismo de longitud del fragmento de restricción, Colombia. Analysis of polymorphisms in the trypanothione reductase and cruzipain genes in Colombian strains of Trypanosoma cruziIntroduction. Genetic studies of Trypanosoma cruzi have tried to establish relations between genetic variants and their biological characteristics, such as clinical manifestations, host or geographic origin. However, much controversy exists on the associations between the commonly used DNA markers with group, clinical characteristics and disease epidemiology. Objective. In this study determined the variability of the genes that code for the proteins trypanothione reductase and cruzipain, both involved in the infection and survival of the parasite in the mammalian host, was studied and the association between genetic polymorphism and biological and geographic sources in Colombian T. cruzi strains was examined. Materials and methods. The genotypes for each of six SNPs (single nucleotide polymorphisms) for trypanothione reductase and eight SNPs for cruzipain genes were identified by polymerase chain reaction-restriction fragment length polymorphism.in 36 T. cruzi Colombian stocks from several regions and bi...

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The major cysteine proteinase (cruzipain) from Trypanosoma cruzi is encoded by multiple polymorphic tandemly organized genes located on different chromosomes

Cited by 167 publications

References 20 publications

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

Análisis de polimorfismos en los genes tripanotión reductasa y cruzipaína en cepas colombianas de Trypanosoma cruzi

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