Evolution of enzyme functionality in the flavin-containing monooxygenases

BAILLEUL, GAUTIER; YANG, GUANG; NICOLL, CALLUM R.; MATTEVI, ANDREA; FRAAIJE, MARCO W.; MASCOTTI, MARIA LAURA

NATURE COMMUNICATIONS

Springer Nature

Año: 2023 vol. 14

2041-1723

Among the molecular mechanisms of adaptation in biology, enzyme func-tional diversification is indispensable. By allowing organisms to expand theircatalytic repertoires and adopt fundamentally different chemistries, animalscan harness or eliminate new-found substances and xenobiotics that they areexposed to in new environments. Here, we explore the flavin-containingmonooxygenases (FMOs) that are essential for xenobiotic detoxification.Employing a paleobiochemistry approach in combination with enzymologytechniques we disclose the set of historical substitutions responsible for thefamily’s functional diversification in tetrapods. Remarkably, a few amino acidreplacements differentiate an ancestral multi-tasking FMO into a more spe-cialized monooxygenase by modulating the oxygenating flavin intermediate.Our findings substantiate an ongoing premise that enzymatic function hingeson a subset of residues that is not limited to the active site core.