Abstract
Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.
Highlights
The synergy between statin treatments and pharmacological or genetic interference with the parasite isoprenoid pathway. It was performed in vivo experiments which demonstrated to be possible to cure mice with atorvastatin from a lethal infection with the TgFPPs mutants. These results suggest that Toxoplasma salvages FPP and GGPP from the vertebrate host and so it relies on both endogenous and human isoprenoid biosynthesis [10]
If FPP is condensed with isopentenyl pyrophosphate (IPP) once again, geranylgeranyl pyrophosphate (GGPP) is formed, a reaction catalyzed by the enzyme GGPP synthase
Menaquinone in Parasitic Protozoa In P. falciparum, MQ-4 biosynthesis has been characterized by Tonhosolo et al [60], but no putative enzymes have been identified for the biosynthesis of this compound
Summary
Protozoa are known to be etiological agents of important diseases such as Chagas disease (Trypanosoma cruzi), African human trypanosomiasis (Trypanosoma brucei), severe leishmaniasis (Leishmania spp.), malaria (Plasmodium spp.), and severe coccidiosis [1,2]. Monoaxenic protozoans, such as Giardia spp. or Cryptosporidium spp., which are able to survive in the vertebrate digestive system as well as in host-free environments based on resistance stage [8] Other parasites, such as Trypanosoma spp., Leishmania spp., and Plasmodium spp., possess heteroxenic cycles and, are able to survive in different organisms [8,9,10]. Trypanosoma brucei is subjected to periods of nutritional stress in the invertebrate host, and it is known that Giardia intestinalis is extremely well adapted for survival in environments with low oxygen saturation [18,19] These adaptive mechanisms include genes and metabolic pathways from, typically, bacteria, eukaryotic heterotrophs, and photosynthetic organisms.
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