Mechanism of action of a flavin-containing monooxygenase

Subramaniam Eswaramoorthy, Jeffrey B. Bonanno, Stephen K. Burley, Subramanyam Swaminathan

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Elimination of nonnutritional and insoluble compounds is a critical task for any living organism. Flavin-containing monooxygenases (FMOs) attach an oxygen atom to the insoluble nucleophilic compounds to increase solubility and thereby increase excretion. Here we analyze the functional mechanism of FMO from Schizosaccharomyces pombe using the crystal structures of the wild type and protein-cofactor and protein-substrate complexes. The structure of the wild-type FMO revealed that the prosthetic group FAD is an integral part of the protein. FMO needs NADPH as a cofactor in addition to the prosthetic group for its catalytic activity. Structures of the protein-cofactor and protein-substrate complexes provide insights into mechanism of action. We propose that FMOs exist in the cell as a complex with a reduced form of the prosthetic group and NADPH cofactor, readying them to act on substrates. The 4α-hydroperoxyflavin form of the prosthetic group represents a transient intermediate of the monooxygenation process. The oxygenated and reduced forms of the prosthetic group help stabilize interactions with cofactor and substrate alternately to permit continuous enzyme turnover.

Original languageEnglish (US)
Pages (from-to)9832-9837
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number26
DOIs
StatePublished - Jun 27 2006
Externally publishedYes

Fingerprint

dimethylaniline monooxygenase (N-oxide forming)
Proteins
NADP
Flavin-Adenine Dinucleotide
Schizosaccharomyces
Solubility
Oxygen
Enzymes

Keywords

  • Methimazole
  • Three-dimensional structure
  • Xenobiotics

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Mechanism of action of a flavin-containing monooxygenase. / Eswaramoorthy, Subramaniam; Bonanno, Jeffrey B.; Burley, Stephen K.; Swaminathan, Subramanyam.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 26, 27.06.2006, p. 9832-9837.

Research output: Contribution to journalArticle

Eswaramoorthy, Subramaniam ; Bonanno, Jeffrey B. ; Burley, Stephen K. ; Swaminathan, Subramanyam. / Mechanism of action of a flavin-containing monooxygenase. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 26. pp. 9832-9837.
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