Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Abstract

Flavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

Keywords: aging; atherosclerosis; flavin-containing monooxygenase (FMO); flavoprotein; iron; metabolism; neurodegenerative disease; oxidation–reduction (redox); sulfur; trimethylamine–N-oxide (TMAO); xenobiotic; xenobiotic metabolism.

Figure 1.

FMO catalytic cycle with canonical hFMO3 substrate TMA shown. * indicates candidate rate-limiting steps. ** indicates site where H₂O₂/O₂⁻ leakage may occur. Adapted from , Copyright © 2005 Elsevier B.V.

Figure 2.

Summary of current knowledge about the regulation and broader role of FMOs. The green box (lower left) depicts known regulators of FMO transcription. The white box (upper left) and arrow (center) show both observed (✓) and hypothetical (?) reactions and mechanisms of FMOs, leading to the broader effects in the red box (right). Redox refers to changes in oxidation/reduction balance resulting from changes to the NADPH/NADP⁺ ratio and/or increased production of hydrogen peroxide.