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    • br The presence of an active glyoxalase pathway

    2022-05-25


    The presence of an active glyoxalase pathway in an apicomplexan parasite was first reported in Plasmodium falciparum-infected erythrocytes (Vander Jagt et al., 1990). Some years later, glyoxalase I and both glyoxalase II enzymes were characterized in this parasite (Akoachere et al., 2005, Iozef et al., 2003). P. falciparum has one GLO1 gene encoding for an active cytosolic glyoxalase I enzyme (Urscher et al., 2010). Its genome also contains a gene coding for a glyoxalase I-like protein (GILP). This enzyme is unique in malarial parasites and seems to be located in the apicoplast but does not exhibit typical GLO1 activity (Akoachere et al., 2005, Urscher et al., 2011). In P. falciparum there are two glyoxalase II enzymes, one cytosolic and another containing an apicoplast targeting sequence (Akoachere et al., 2005, Urscher et al., 2010, Urscher et al., 2011). Glyoxalase I enzymes are characteristically homodimers (with 16–18kDa per monomer), but exceptions are found in Saccharomyces cerevisiae (Marmstal et al., 1979) and Plasmodium falciparum (Iozef et al., 2003) where GLO1 are monomeric with two active sites. These proteins are most probably the result of subunit fusion from smaller homodimeric glyoxalases (Iozef et al., 2003). The P. falciparum zinc-dependent glyoxalase I is a 42.4kDa protein (UniProt Q71KM3) with two functional active sites displaying different affinities toward the glutathione-derived substrate and allosterically coupled (Deponte et al., 2007, Urscher et al., 2011). Enzyme allostery is often associated with a regulatory function. In this case, the enzyme responds differentially to lower or higher methylglyoxal intracellular concentrations, associated with the environment changes inherent to the parasite complex life ropinirole hydrochloride (Deponte et al., 2007). P. falciparum parasites have two active glyoxalase II isozymes: one cytosolic (cGLO2, 30.5kDa; UniProt C0H490) and another targeted to the apicoplast (tGLO2, 38.4kDa; UniProt Q8I5Y8), both with a binuclear metal center (Akoachere et al., 2005). The cytosolic GLO2 follows a Theorell-Chance Bi Bi catalytic mechanism, being d-lactate released first and glutathione the second product released (Urscher and Deponte, 2009). In vitro this enzyme can form dimers that, if proven to occur in vivo, might be associated with a regulatory function or a role in signaling (Urscher et al., 2010). Malarial parasites have a complex life cycle, alternating between a vector (mosquito) and a human host. There are different morphological stages, sporozoite (the infectious form), merozoite (erythrocyte invading stage), trophozoite (erythrocyte multiplying form) and gametocyte (sexual stages), each with their own specific proteome (Florens et al., 2002). Concerning the expression of both glyoxalases during the life cycle stages of P. falciparum, the only information available is from global proteomic studies (Florens et al., 2002, Lasonder et al., 2002, Le Roch et al., 2004). Glyoxalase I expression varies depending on the study, either in the gametocytes stage (Lasonder et al., 2002) or in sporozoites and merozoites (Florens et al., 2002). Targeted GLO2 was found to be expressed only in trophozoites and gametocytes (Florens et al., 2002, Le Roch et al., 2004). No expression information was available for cGLO2. To date, the glyoxalase pathway was never studied in Toxoplasma gondii, but putative genes for both glyoxalase I and II enzymes were found in this parasite's genome (ToxoDB.org; Xia et al., 2008). Glyoxalase I has approximately 38.5kDa (UniProt B6KH64; Xia et al., 2008), most probably being a monomeric enzyme like the P. falciparum homolog. Unlike P. falciparum, only one glyoxalase II encoding gene is present in the T. gondii genome (UniProt B6KU69). In a previous study to identify the whole proteome of T. gondii in the tachyzoite life cycle stage, this 43.5-kDa protein was found in the mitochondrion (Xia et al., 2008). However, it does not have a signal peptide in this organelle, and there are no predictions of such a location based on available bioinformatics tools. A detailed characterization of both enzymes will be needed in order to shed light on the functionality and importance of the glyoxalase pathway in these parasites.