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BIOLOGICAL SCIENCES / BIOCHEMISTRY
Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase
*Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy; and Laboratory of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Edited by David P. Ballou, University of Michigan, Ann Arbor, MI, and accepted by the Editorial Board March 7, 2008 (received for review January 28, 2008)
Flavin-containing monooxygenases (FMOs) are, after cytochromes P450, the most important monooxygenase system in humans and are involved in xenobiotics metabolism and variability in drug response. The x-ray structure of a soluble prokaryotic FMO from Methylophaga sp. strain SK1 has been solved at 2.6-Å resolution and is now the protein of known structure with the highest sequence similarity to human FMOs. The structure possesses a two-domain architecture, with both FAD and NADP+ well defined by the electron density maps. Biochemical analysis shows that the prokaryotic enzyme shares many functional properties with mammalian FMOs, including substrate specificity and the ability to stabilize the hydroperoxyflavin intermediate that is crucial in substrate oxygenation. On the basis of their location in the structure, the nicotinamide ring and the adjacent ribose of NADP+ turn out to be an integral part of the catalytic site being actively engaged in the stabilization of the oxygenating intermediate. This feature suggests that NADP(H) has a moonlighting role, in that it adopts two binding modes that allow it to function in both flavin reduction and oxygen reactivity modulation, respectively. We hypothesize that a relative domain rotation is needed to bring NADP(H) to these distinct positions inside the active site. Localization of mutations in human FMO3 that are known to cause trimethylaminuria (fish-odor syndrome) in the elucidated FMO structure provides a structural explanation for their biological effects.
drug metabolism | trimethylaminuria | oxygen
Present address: Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, W423J Chicago, IL 60637.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. D.P.B. is a guest editor invited by the Editorial Board.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2vq7 and 2vqb).
This article contains supporting information online at www.pnas.org/cgi/content/full/0800859105/DCSupplemental.
To whom correspondence should be addressed. E-mail: mattevi{at}ipvgen.unipv.it
© 2008 by The National Academy of Sciences of the USA
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