Beyond active site residues: overall structural dynamics control catalysis in flavin-containing and heme-containing monooxygenases

• Published in: Current opinion in structural biology Vol. 59; pp. 29 - 37
• Main Authors: Fürst, Maximilian JLJ, Fiorentini, Filippo, Fraaije, Marco W
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2019
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2019.01.019

[Display omitted] •Monooxygenases (MOs) face a challenging reaction, requiring the coordination of three substrates by the same active site.•To address this challenge, these enzymes evolved various strategies involving structural flexibility.•Flavoprotein MOs use mobile flavin and nicotinamide cofactors to reshape the active site and coordinate catalysis.•In cytochrome P450s, highly flexible elements throughout the structure are pivotal to substrate selection and acceptance. Monooxygenases (MOs) face the challenging reaction of an organic target, oxygen and a cofactor – most commonly heme or flavin. To correctly choreograph the substrates spatially and temporally, MOs evolved a variety of strategies, which involve structural flexibility. Besides classical domain and loop movements, flavin-containing MOs feature conformational changes of their flavin prosthetic group and their nicotinamide cofactor. With similar mechanisms emerging in various subclasses, their generality and involvement in selectivity are intriguing questions. Cytochrome P450 MOs are often inherently plastic and large movements of individual segments throughout the entire structure occur. As these complicated and often unpredictable movements are largely responsible for substrate uptake, engineering strategies for these enzymes were mostly successful when randomly mutating residues across the entire structure.