β-Carotene alleviates substrate inhibition caused by asymmetric cooperativity

Jieren Liao, Umar F. Shahul Hameed, Timothy D. Hoffmann, Elisabeth Kurze, Guangxin Sun, Wieland Steinchen, Alessandro Nicoli, Antonella Pizio, Christina Kuttler, Chuankui Song, Dragana A. M. Catici, Farhah Assaad-Gerbert, Thomas Hoffmann, Stefan T. Arold and Wilfried G. Schwab ()
Additional contact information
Jieren Liao: Technical University of Munich
Umar F. Shahul Hameed: King Abdullah University of Science and Technology (KAUST)
Timothy D. Hoffmann: Technical University of Munich
Elisabeth Kurze: Technical University of Munich
Guangxin Sun: Technical University of Munich
Wieland Steinchen: Philipps-University Marburg
Alessandro Nicoli: Leibniz Institute for Food Systems Biology at the Technical University of Munich
Antonella Pizio: Leibniz Institute for Food Systems Biology at the Technical University of Munich
Christina Kuttler: Information and Technology
Chuankui Song: Anhui Agricultural University
Dragana A. M. Catici: Technical University of Munich
Farhah Assaad-Gerbert: Technical University of Munich
Thomas Hoffmann: Technical University of Munich
Stefan T. Arold: King Abdullah University of Science and Technology (KAUST)
Wilfried G. Schwab: Technical University of Munich

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Enzymes are essential catalysts in biological systems. Substrate inhibition, once dismissed, is now observed in 20% of enzymes1 and is attributed to the formation of an unproductive enzyme-substrate complex, with no structural evidence of unproductivity provided to date1–6. This study uncovers the molecular mechanism of substrate inhibition in tobacco glucosyltransferase NbUGT72AY1, which transfers glucose to phenols for plant protection. The peculiarity that β-carotene strongly attenuates the substrate inhibition of NbUGT72AY1, despite being a competitive inhibitor, allows to determine the conformational changes that occur during substrate binding in both active and substrate-inhibited complexes. Crystallography reveals structurally different ternary enzyme-substrate complexes that do not conform to classical mechanisms. An alternative pathway suggests substrates bind randomly, but the reaction occurs only if a specific order is followed (asymmetric cooperativity). This unreported paradigm explains substrate inhibition and reactivation by competitive inhibitors, opening new research avenues in metabolic regulation and industrial applications.

Date: 2025
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DOI: 10.1038/s41467-025-58259-7

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