Abstract
Glycolysis and glyconeogenesis play crucial roles in the ATP supply and synthesis of glycoconjugates, important for the viability and virulence, respectively, of the human-pathogenic stages of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. These pathways are, therefore, candidate targets for antiparasite drugs. The glycolytic/gluconeogenic enzyme enolase is generally highly conserved, with similar overall fold and identical catalytic residues in all organisms. Nonetheless, potentially important differences exist between the trypanosomatid and host enzymes, with three unique, reactive residues close to the active site of the former that might be exploited for the development of new drugs. In addition, enolase is found both in the secretome and in association with the surface of Leishmania spp. where it probably functions as plasminogen receptor, playing a role in the parasite's invasiveness and virulence, a function possibly also present in the other trypanosomatids. This location and possible function of enolase offer additional perspectives for both drug discovery and vaccination.
Highlights
All known organisms belonging to the Trypanosomatidae, a family of protists within the order Kinetoplastida, are parasites of vertebrates, invertebrates, or plants
Since enolase catalyzes the reversible conversion of 2PGA into PEP, the forward reaction being the ninth step of glycolysis and the reverse reaction being the first one of gluconeogenesis, an organism, tissue, or cell may need to optimize the properties of this enzyme in such a way that the flux in either one or the other direction is facilitated, dependent on whether it should adapt its metabolism to performing the catabolic or anabolic process
In bloodstream-form T. brucei, enolase is involved in glycolysis, a process crucial for the ATP supply of the parasites
Summary
All known organisms belonging to the Trypanosomatidae, a family of protists within the order Kinetoplastida, are parasites of vertebrates, invertebrates, or plants. Studies of the metabolic pathways essential for parasite survival and the mechanisms by which the trypanosomatids establish an infection in the human host are important both for future chemotherapy and vaccination. Such studies may identify molecules—unique or at least highly different from host molecules—that are interesting as candidate drug targets and the subsequent discovery of selective inhibitors of these molecules to combat the parasitic diseases, as well as molecules that could be exploited as potential antigens to induce immunoprotection against the trypanosomiases and leishmaniases. We will argue that enolase, a protein involved both as enzyme in glycolysis and gluconeogenesis, metabolic processes essential for T. brucei, T. cruzi, and Leishmania spp., and probably as a virulence factor in the pathogenesis caused by Leishmania spp., T. cruzi and possibly T. brucei, represents both an interesting drug target and vaccine candidate
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