A genome-scale metabolic model of parasitic whipworm

• Published in: Nature communications Vol. 14; no. 1; p. 6937
• Main Authors: Bay, Ömer F., Hayes, Kelly S., Schwartz, Jean-Marc, Grencis, Richard K., Roberts, Ian S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-10-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 631/154/556; 631/45/607/1168; 631/553/2710; 64/60; Amino acids; Animals; Auranofin; Enzymes; Genomes; Glutathione; Glutathione reductase; Glutathione Reductase - metabolism; Host-Pathogen Interactions; Humanities and Social Sciences; Metabolic pathways; Metabolism; Metabolites; Mice; multidisciplinary; Parasites; Predictions; Reductases; Science; Science (multidisciplinary); Survival; Thioredoxin; Trichuris - genetics; Trichuris - metabolism; Trichuris muris; Tryptophan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42552-4

Genome-scale metabolic models are widely used to enhance our understanding of metabolic features of organisms, host-pathogen interactions and to identify therapeutics for diseases. Here we present iTMU798, the genome-scale metabolic model of the mouse whipworm
Trichuris muris
. The model demonstrates the metabolic features of
T. muris
and allows the prediction of metabolic steps essential for its survival. Specifically, that Thioredoxin Reductase (TrxR) enzyme is essential, a prediction we validate in vitro with the drug auranofin. Furthermore, our observation that the
T. muris
genome lacks
gsr-1
encoding Glutathione Reductase (GR) but has GR activity that can be inhibited by auranofin indicates a mechanism for the reduction of glutathione by the TrxR enzyme in
T. muris
. In addition, iTMU798 predicts seven essential amino acids that cannot be synthesised by
T. muris
, a prediction we validate for the amino acid tryptophan. Overall, iTMU798 is as a powerful tool to study not only the
T. muris
metabolism but also other
Trichuris spp
. in understanding host parasite interactions and the rationale design of new intervention strategies.
In this work, Bay et al describe the construction of the first genome-scale metabolic model for the parasitic whipworm,
Trichuris muris
and use it to identify novel metabolic pathways and predict critical enzymes and essential metabolites for worm survival.