STUDY OF THE CUPROPROTEINS TcSCO-A AND THEIR CONTRIBUTION TO THE FUNCTIONING OF THE CYTOCHROME C OXIDASE OF Trypanosoma cruzi

ACOSTA OVIEDO H; MERLI ML; MEDIAVILLA MG*; CRICCO JA

Rosario

Congreso; LIX Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2023

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular (SAIB)

In Trypanosoma cruzi, the etiologic agent of Chagas disease, the presence of a branched respiratory chain with cytochrome c oxidase (COX) type aa3 as the main terminal oxidase has been described(1-3). Recently, the importance of COX was demonstrated since the impairment of the enzyme activity compromised parasite survival, proliferation, and infectivity(4).COX is a multiprotein complex in whose assembly various proteins participate(5). Among them are the SCO (synthesis of cytochrome c oxidase) metallochaperones, belonging to the superfamily ofthioredoxins and whose function has been shown to be essential not only for their participation in the supply of copper for the assembly of the catalytic nucleus of COX, but also in copper homeostasis and cellular redox homeostasis in various organisms(6-9).In our laboratory we have identified, through bioinformatic analysis, 3 genes that would encode for an electron transport protein SCO1/SCO2 like (BCY84_03573) that we named TcSCO-A and two cytochrome c oxidase assembly factors (BCY84_19910) and (BCY84_01670) named as TcSCO-B and TcSCO-C, respectively. The three proteins present a characteristic CXXXC motif of cuproproteins and thioredoxins, despite presenting a low percentage of identity between them: 43.8% (TcSCO-A/TcSCO-B), 32.4% (TcSCO-A/TcSCO-C), 30.4% (TcSCO-B/TcSCO-C) and not showing a hylogenetic relationship with other eukaryotes, including its two hosts: arthropod and chordata.The overexpression of TcSCO-A and TcSCO-B in Dm28c epimastigotes transfected with pTcINDEX/TcSCO-A and pTcINDEX/TcSCO-B produced a delay in growth which was increased in the presence of 250 µM Cu(II) and the copper chelator Neocuproine. Incubations of epimastigotesoverexpressing TcSCO-A failed to reverse the effect of elesclomol, an anticancer drug recognized to be an inducer of oxidative stress and producer of cuproptosis in cancer cells10. These preliminary results position TcSCO-A as an interesting target for the development of future drugs with trypanocidal activity.References: (1)doi: 10.1017/S1462399409001252; (2)Rev Inst Med Trop Sao Paulo. 1964;6:93-100.; (3)J Parasitol. 1960;46:529-39.; (4)doi: 10.1007/978-1-4899-1651-8_7; (5)doi: 10.1126/science.1110289; (6)doi: 10.1016/0305-0491(86)90016-7; (7)doi: 10.1016/j.pt.2006.08.007; (8)doi: 10.1007/s10863-011-9369-0; (9)doi: 10.1042/BCJ20170084; 10doi: 10.1186/s13046-022-02485-0