2vqb: Difference between revisions
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'''BACTERIAL FLAVIN-CONTAINING MONOOXYGENASE IN COMPLEX WITH NADP: SOAKING IN AERATED SOLUTION''' | '''BACTERIAL FLAVIN-CONTAINING MONOOXYGENASE IN COMPLEX WITH NADP: SOAKING IN AERATED SOLUTION''' | ||
==Overview== | |||
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-A 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. | |||
==About this Structure== | ==About this Structure== | ||
2VQB is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Methylophaga_sp._sk1 Methylophaga sp. sk1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VQB OCA]. | 2VQB is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Methylophaga_sp._sk1 Methylophaga sp. sk1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VQB OCA]. | ||
==Reference== | |||
Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase., Alfieri A, Malito E, Orru R, Fraaije MW, Mattevi A, Proc Natl Acad Sci U S A. 2008 May 6;105(18):6572-7. Epub 2008 Apr 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18443301 18443301] | |||
[[Category: Methylophaga sp. sk1]] | [[Category: Methylophaga sp. sk1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Alfieri, A]] | [[Category: Alfieri, A.]] | ||
[[Category: Fraaije, M W.]] | [[Category: Fraaije, M W.]] | ||
[[Category: Malito, E]] | [[Category: Malito, E.]] | ||
[[Category: Mattevi, A]] | [[Category: Mattevi, A.]] | ||
[[Category: Orru, R.]] | [[Category: Orru, R.]] | ||
[[Category: Drug metabolism]] | [[Category: Drug metabolism]] | ||
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[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Oxygen]] | [[Category: Oxygen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May 14 11:40:23 2008'' | ||
Revision as of 11:40, 14 May 2008
BACTERIAL FLAVIN-CONTAINING MONOOXYGENASE IN COMPLEX WITH NADP: SOAKING IN AERATED SOLUTION
OverviewOverview
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-A 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.
About this StructureAbout this Structure
2VQB is a Single protein structure of sequence from Methylophaga sp. sk1. Full crystallographic information is available from OCA.
ReferenceReference
Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase., Alfieri A, Malito E, Orru R, Fraaije MW, Mattevi A, Proc Natl Acad Sci U S A. 2008 May 6;105(18):6572-7. Epub 2008 Apr 28. PMID:18443301 Page seeded by OCA on Wed May 14 11:40:23 2008