Díaz-Viraqué Florencia, Chiribao María Laura, Paes-Vieira Lisvane, Machado Matias R, Faral-Tello Paula, Tomasina Ramiro, Trochine Andrea, Robello Carlos
Laboratorio de Interacciones Hospedero Patógeno, Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay.
Departamento de Bioquímica, Facultad de Medicina Universidad de la República, Montevideo 11400, Uruguay.
Pathogens. 2023 Jan 5;12(1):85. doi: 10.3390/pathogens12010085.
Chagas disease is a zoonotic infectious disease caused by the protozoan parasite . It is distributed worldwide, affecting around 7 million people; there is no effective treatment, and it constitutes a leading cause of disability and premature death in the Americas. Only two drugs are currently approved for the treatment, Benznidazole and Nifurtimox, and both have to be activated by reducing the nitro-group. The aldo-keto reductase (AKR) has been related to the metabolism of benznidazole. AKR has been extensively studied, being most efforts focused on characterizing its implication in trypanocidal drug metabolism; however, little is known regarding its biological role. Here, we found that AKR is confined, throughout the entire life cycle, into the parasite mitochondria providing new insights into its biological function. In particular, in epimastigotes, AKR is associated with the kinetoplast, which suggests additional roles of the protein. The upregulation of AKR, which does not affect OYE expression, was correlated with an increase in PGFα, suggesting that this enzyme is related to PGFα synthesis in . Structural analysis showed that AKR contains a catalytic tetrad conserved in the AKR superfamily. Finally, we found that AKR is also involved in Nfx metabolization.
恰加斯病是一种由原生动物寄生虫引起的人畜共患传染病。它在全球范围内分布，影响着约700万人；目前没有有效的治疗方法，它是美洲导致残疾和过早死亡的主要原因。目前仅有两种药物被批准用于治疗，即苯硝唑和硝呋替莫，且两者都必须通过还原硝基来激活。醛酮还原酶（AKR）与苯硝唑的代谢有关。AKR已被广泛研究，大多数研究致力于表征其在杀锥虫药物代谢中的作用；然而，关于其生物学作用却知之甚少。在这里，我们发现AKR在整个生命周期中都局限于寄生虫的线粒体中，这为其生物学功能提供了新的见解。特别是，在前鞭毛体中，AKR与动质体相关，这表明该蛋白还有其他作用。AKR的上调（不影响OYE表达）与PGFα的增加相关，这表明该酶与[此处原文可能有误，推测应为寄生虫体内]的PGFα合成有关。结构分析表明，AKR含有在AKR超家族中保守的催化四联体。最后，我们发现AKR也参与硝呋替莫的代谢。
