Comparative analyses of parasites with a comprehensive database of genome-scale metabolic models
Fig 6
Predicting metabolic function.
(A): Advantage of network-based approaches. Metabolic models include hypothetical functions (i.e. the enzyme encoded by gene2) that are unsupported by direct genetic evidence but may be indirectly required based on biochemical evidence. These functions are added through gapfilling. Using models augments our analysis beyond mere genetic comparisons: some enzymes may not be discovered in the genome despite being necessary for biochemical observations made and are included in these models. (B): Defining metabolic capacities. With our gapfilled models, we can identify if metabolites are consumed and/or produced. (C): Experimentally-derived metabolic functions. We compiled data providing evidence for consumption or production of select metabolites from the literature (S1 Table). Consumed metabolites are imported by the parasite from the extracellular environment (e.g. the in vitro growth medium). Produced metabolites are synthesized by the parasite even when the metabolite is not in the extraceullar environment. See Additional Information: Online Methods for more detail. Data are sparse. (D): Analogous in silico metabolic capacity. Inferred metabolic capacity of each organism from Panel C for every metabolite from panel C. Data from panel C was used to gapfill reconstructions to generate data presented in Panel D (see Fig 2A for methods). See Panel B for definitions. Metabolites that are neither produced nor consumed are consumed intracellularly but are not taken up from the extracellular environment. Metabolites noted as ‘complex or unknown’ here are represented by multiple metabolite identifiers in the reconstructions (e.g., lactate is measured experimentally, but could represent both D-lactate and L-lactate within the reconstruction). (E-G): Example gapfilled functions in the Vitamin B6 pathway. These reactions were added to support the observed metabolic functions in Panel C or to support in silico growth. Panel E shows L-alanine-alpha-keto acid aminotransferase (ASPTA6, added to 58 reconstructions), Panel F shows pyridoxamine-pyruvic transaminase (PDYXPT_c, added to 64 reconstructions), and Panel G shows pyridoxamine oxidase (PYDXO, named pyridoxal oxidase in BiGG, added to 90 reconstructions). Note, a deaminateing pyridoxamine:oxygen oxidoreductase (PYDXO_1) is also added to 12 reactions to interconvert pyridoxal and pyridoxamine.