CONICET | Buscador de Institutos y Recursos Humanos

Heme A is an essential cofactor for eukaryotic cytochrome c oxidase. This cofactor is derived from heme B via two enzymatic reactions. The first one, catalyzed by heme O synthase (HOS, Cox10p), results in the conversion of the vinyl group on pyrrole ring A into a 17-hydroxyethylfarnesyl moiety. In the second transformation, heme A synthase (HAS, Cox15p) catalyze the oxidation of the methyl group on pyrrole ring D into an aldehyde. The biosynthesis of this cofactor is carry out in mitochondria and HOS and HAS enzymes are encoded by nuclear genes COX10 y COX15 respectively. Although, T. cruzi does not synthesize heme de novo, we have identified by sequence homology search, the open reading frames for the Cox10p and Cox15p enzymes. The T. cruziCOX10 ORF was cloned and expressed in S. cerevisiae cox10 knock out cells (cox10D) that are respiratory deficient and show impaired heme A biosynthesis. The expression of TcCox10 in cox10D cells suppresses the phenotype of the knock out cells, restoring the standard levels of respiratory activity and mitochondrial heme A concentration. Impaired heme A biosynthesis causes a non functional cytochrome c oxidase enzyme and it is related to several syndromes and diseases. Notwithstanding T. cruzi does not synthesize heme, the presence of Cox10p and Cox15p enzymes and cytochrome c suggest that this cofactor has to be imported and transported to mitochondria. Later, in this organelle, it is modified in order to be utilized by hemoproteins involved in key processes. The study of the heme transport and mitochondrial modifications would contribute to identify essential metabolic routes in trypanosomatids.