It cycles

It cycles GS-1101 solubility dmso between invertebrate and vertebrate hosts, presenting several developmental stages and adapting its metabolism to changing nutrient availability [epimastigotes and metacyclic trypomastigotes in the insect vector and amastigotes and trypomastigotes in the mammalian host (Brener, 1973; Almeida-de-Faria et al., 1999)]. Trypanosoma cruzi, like other trypanosomatids,

has requirements for several essential cofactors, one of which is heme. Biochemical studies have demonstrated the absence of a complete heme biosynthetic pathway (revisited in Korenýet al. 2010). This fact was corroborated by the absence of the conserved pathway in its genomic sequence (El-Sayed et al., 2005). Hence, these trypanosomatids are dependent on the uptake of this compound from CHIR-99021 in vivo their environment. After being imported, heme is transported and inserted into target proteins, which are distributed throughout different subcellular compartments. The mitochondrion is one of the most relevant heme-protein-containing organelles, and it includes the respiratory chain complexes. One characteristic of these parasites is their single and usually well-developed

mitochondrion, which presents functional and structural changes depending on the stages of its life cycle (de Souza et al., 2009). The presence of electron transport from complex II to complex IV has been demonstrated, but the contribution of complex I (NADH : ubiquinone oxidoreductase) to energy metabolism remains controversial (Opperdoes & Michels, 2008; Carranza et al., 2009). Biochemical studies developed in T. cruzi epimastigotes showed that the main terminal oxidase is the aa3 type (Affranchino et al., 1986), the canonical cytochrome c oxidase for eukaryotic cells. Additionally, proteomic studies demonstrated the presence of subunits of complex IV (cytochrome c oxidase, CcO enzyme), other components of the Rebamipide respiratory chain and subunits of the FoF1

ATPase (complex V) (Parodi-Talice et al., 2007; Ferella et al., 2008). In nonphotosynthetic eukaryotic cells, the complete heme synthetic pathway starts and finishes in the mitochondria. Trypanosoma cruzi lacks the heme biosynthetic route, and the transport and distribution of this cofactor are uncharacterized. One interesting open question is how heme A, the essential cofactor for eukaryotic CcO enzymes, is synthesized in this organism. In eukaryotic cells, heme A biosynthesis proceeds in the mitochondria. It is catalyzed by two enzymes, heme O synthase (HOS or Cox10) and heme A synthase (HAS or Cox15), which are both integral to the mitochondrial inner membrane (Barros & Tzagoloff, 2002). HOS catalyzes the synthesis of heme O by the conversion of the vinyl group on pyrrole ring A in heme B into a 17-hydroxyethylfarnesyl moiety. HAS catalyzes the oxidation of the methyl group on pyrrole ring D into an aldehyde, converting heme O into heme A.

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