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Isotope substitution of promiscuous alcohol dehydrogenase reveals origin of substrate preference in transition state

The origin of substrate preference in promiscuous enzymes was investigated by enzyme isotope labeling of the alcohol dehydrogenase from Geobacillus stearothermophilus (BsADH). At physiological temperature, protein dynamic coupling to the reaction coordinate was insignificant. However, the extent of dynamic coupling was highly substrate‐dependent at lower temperatures. For benzyl alcohol, an enzyme isotope effect larger than unity was observed, whereas the enzyme isotope effect was close to unity for isopropanol. Frequency motion analysis on the transition states revealed that residues surrounding the active site undergo substantial displacement during catalysis for sterically bulky alcohols. BsADH prefers smaller substrates, which cause less protein friction along the reaction coordinate and reduced frequencies of dynamic recrossing. This hypothesis allows a prediction of the trend of enzyme isotope effects for a wide variety of substrates.

Autoren:   Rudolf K Allemann, J Javier Ruiz-Pernia, Louis Luk, Inaki Tunon, Vicent Moliner, Enas Behiry
Journal:   Angewandte Chemie International Edition
Jahrgang:   2018
Seiten:   n/a
DOI:   10.1002/anie.201712826
Erscheinungsdatum:   17.01.2018
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