Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known
whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate
is partially converted to mesaconate intracellularly and that
mesaconate accumulation in macrophage activation depends
on prior itaconate synthesis. When added to human cells in
supraphysiological concentrations, all three isomers reduce
lactate levels, whereas itaconate is the strongest succinate
dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino
acid metabolism, modulate cytokine/chemokine release and
reduce interferon signalling, oxidative stress and the release
of viral particles. Of the three isomers, citraconate is the
strongest electrophile and nuclear factor-erythroid 2-related
factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of
itaconate by cis-aconitate decarboxylase (ACOD1), probably
by competitive binding to the substrate-binding site. These
results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate
as the first naturally occurring ACOD1 inhibitor