Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Abstract

The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection. The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection. Members of the Apicomplexa encompass a large number of parasites exhibiting a great level of diversity in their life cycles, with morphologically distinct stages in one or more hosts. The phylum includes coccidians, hemosporidians, piroplasms, Cryptosporidia, and gregarines that occupy divergent niches (1Plattner F. Soldati-Favre D. Hijacking of host cellular functions by the Apicomplexa.Annu. Rev. Microbiol. 2008; 62 (18785844): 471-48710.1146/annurev.micro.62.081307.162802Crossref PubMed Scopus (82) Google Scholar). Toxoplasma gondii is the most successful zoonotic parasite of the cyst-forming subclass of coccidians. The proliferative tachyzoites infect and replicate in most cell types and are responsible for an acute infection, whereas the dormant cyst-forming bradyzoites are responsible for chronic infection, predominantly in the brain and striated muscles (2Dubey J.P. Lindsay D.S. Speer C.A. 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In a recent study,3 a well-curated computational genome-scale model, iTgo (in silico T. gondii), was generated. iTgo contains 556 metabolic genes and integrates all available data sets to serve as a valuable platform for model-guided investigations. To harmonize the model with the genome-wide fitness scores for metabolic genes, additional constraints on substrate availabilities from the host as well as reaction utilization based on transcriptomics data were applied (16Stanway R.R. Bushell E. Chiappino-Pepe A. Roques M. Sanderson T. Franke-Fayard B. Caldelari R. Golomingi M. Nyonda M. Pandey V. Schwach F. Chevalley S. Ramesar J. Metcalf T. Herd C. et al.Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.Cell. 2019; 179 (31730853): 1112-112810.1016/j.cell.2019.10.030Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 30Pandey V. Hernandez Gardiol D. Chiappino Pepe A. Hatzimanikatis V. 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Further, the latest observations are discussed in the context of long-standing questions on the roles of the metabolic pathways for latency and their potential as drug targets. Vitamin B1, or thiamine, is an important precursor for its metabolically active form, thiamine pyrophosphate (TPP). TPP acts as a cofactor for enzymes implicated in carbohydrate and amino acid metabolism, such as the PDH complex, 2-oxoglutarate dehydrogenase, pyruvate decarboxylase, and dihydrolipoamide dehydrogenase. In T. gondii, these enzymes are either residents of the secondary endosymbiotic organelle, called the apicoplast, or the mitochondrion, suggesting a need for the cofactor within these subcellular compartments. Like their mammalian host, the parasites do not possess the pathway for thiamine biosynthesis and must therefore acquire it. 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