Specialized aldo-keto reductases trigger complete degradation of mycotoxin deoxynivalenol

The mycotoxin deoxynivalenol (DON) poses severe threats to human and animal well-being globally. Enzymatic degradation is the most effective way to eliminate DON toxicity, yet no catalytic process for complete degradation of DON has been uncovered. Here, we show that a metabolic pathway initiated by C3-epimerization and C8-reduction is responsible for complete degradation of DON in the DON-metabolizing bacterium Nocardioides sp. S5-5. Two horizontally transferred aldo-keto reductase genes, DONepi and DONrd, have evolved to orchestrate C3-epimerization and C8-reduction respectively. Notably, the octameric-structured DONepi alone catalyzes C3-epimerization of DON by steering the rigid-body rotation of the transient 3-keto intermediate for stereoinverting reduction. Moreover, DONrd can catalyze the C8-reduction of DON and its C3-epimerized product 3-epi-DON simultaneously to form C8-hydroxyl products, which facilitates the further degradation by a potential oxidase and other putative enzymes. DONepi expression in transgenic plants confers resistance to DON, representing potential for controlling mycotoxin contamination pre- and postharvest. The mycotoxin deoxynivalenol (DON) threatens global human and animal health. Here, the authors identify two key functional enzymes in a bacterium that initiate the complete degradation of DON to CO2, elucidating their core catalytic mechanisms and biotechnological application potential.