Evolution of enzyme functionality in the flavin-containing monooxygenases

Among the molecular mechanisms of adaptation in biology, enzyme functional diversification is indispensable. By allowing organisms to expand their catalytic repertoires and adopt fundamentally different chemistries, animals can harness or eliminate new-found substances and xenobiotics that they are exposed to in new environments. Here, we explore the flavin-containing monooxygenases (FMOs) that are essential for xenobiotic detoxification. Employing a paleobiochemistry approach in combination with enzymology techniques we disclose the set of historical substitutions responsible for the family's functional diversification in tetrapods. Remarkably, a few amino acid replacements differentiate an ancestral multi-tasking FMO into a more specialized monooxygenase by modulating the oxygenating flavin intermediate. Our findings substantiate an ongoing premise that enzymatic function hinges on a subset of residues that is not limited to the active site core. Detoxification enzymes are crucial for the survival of animals in new environments. Here, the authors study the molecular mechanism behind the catalytic diversification of a major family of tetrapod detoxification enzymes-the FMOs-during evolution.

Automated summary

Enzyme functional diversification is crucial for biological adaptation, allowing organisms to utilize or eliminate new substances and xenobiotics in new environments. This study uses a paleobiochemistry approach and enzymology techniques to uncover the historical substitutions that led to the functional diversification of the FMO family in tetrapods. Few amino acid replacements modulate the oxygenating flavin intermediate, transforming an ancestral multi-tasking FMO into a specialized monooxygenase. This finding highlights the importance of residues beyond the active site core in determining enzymatic function. Detoxification enzymes play a crucial role in the survival of animals in new environments.