4.6 Article

New frontiers in flavin-dependent monooxygenases

Journal

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 699, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2021.108765

Keywords

Flavin motions; Oxygen activation; Conformational changes; Antibiotics; Monooxygenation; Homolytic bond cleavage; Drug target

Funding

  1. National Science Foundation [CHE 2003658]

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Flavin-dependent monooxygenases play important roles in biological processes, with recent research focusing on formation of reactive intermediates and catalytic mechanisms. Novel catalysis by different N-oxidases and their relevance to organisms are discussed. Additionally, some FMOs are crucial for the virulence of human pathogens and have biomedical importance in antibiotic resistance.
Flavin-dependent monooxygenases catalyze a wide variety of redox reactions in important biological processes and are responsible for the synthesis of highly complex natural products. Although much has been learned about FMO chemistry in the last similar to 80 years of research, several aspects of the reactions catalyzed by these enzymes remain unknown. In this review, we summarize recent advancements in the flavin-dependent monooxygenase field including aspects of flavin dynamics, formation and stabilization of reactive species, and the hydroxylation mechanism. Novel catalysis of flavin-dependent N-oxidases involving consecutive oxidations of amines to generate oximes or nitrones is presented and the biological relevance of the products is discussed. In addition, the activity of some FMOs have been shown to be essential for the virulence of several human pathogens. We also discuss the biomedical relevance of FMOs in antibiotic resistance and the efforts to identify inhibitors against some members of this important and growing family enzymes.

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