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000094652 1001_ $$aKachalova, G.
000094652 1101_ $$aDESY$$bExperiments with synchrotron radiation
000094652 245__ $$aCrystallographic snapshots of the complete reaction cycle of nicotine degradation by an amine oxidase of the monoamine oxidase (MAO) family
000094652 260__ $$aWashington, DC$$bAcademy$$c2011
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000094652 440_0 $$0PERI:(DE-600)1461794-8$$aProc. Nat. Acad. Sci. USA$$v108$$x1091-6490$$y12
000094652 500__ $$3Converted on 2013-05-30 15:04
000094652 500__ $$3Converted on 2013-06-21 19:21
000094652 520__ $$aFAD-linked oxidases constitute a class of enzymes which catalyze dehydrogenation as a fundamental biochemical reaction, followed by reoxidation of reduced flavin. Here, we present high-resolution crystal structures showing the flavoenzyme 6-hydroxy-l-nicotine oxidase in action. This enzyme was trapped during catalytic degradation of the native substrate in a sequence of discrete reaction states corresponding to the substrate-reduced enzyme, a complex of the enzyme with the intermediate enamine product and formation of the final aminoketone product. The inactive d-stereoisomer binds in mirror symmetry with respect to the catalytic axis, revealing absolute stereospecificity of hydrogen transfer to the flavin. The structural data suggest deprotonation of the substrate when bound at the active site, an overall binary complex mechanism and oxidation by direct hydride transfer. The amine nitrogen has a critical role in the dehydrogenation step and may activate carbocation formation at the α-carbon via delocalization from the lone pair to σ* C(α)-H. Enzymatically assisted hydrolysis of the intermediate product occurs at a remote (P site) cavity. Substrate entry and product exit follow different paths. Structural and kinetic data suggest that substrate can also bind to the reduced enzyme, associated with slower reoxidation as compared to the rate of reoxidation of free enzyme. The results are of general relevance for the mechanisms of flavin amine oxidases.
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000094652 650_7 $$00$$2NLM Chemicals$$aBacterial Proteins
000094652 650_7 $$054-11-5$$2NLM Chemicals$$aNicotine
000094652 650_7 $$0EC 1.4.3.4$$2NLM Chemicals$$aMonoamine Oxidase
000094652 650_7 $$0EC 1.5.-$$2NLM Chemicals$$aOxidoreductases Acting on CH-NH Group Donors
000094652 650_7 $$0EC 1.5.3.5$$2NLM Chemicals$$a6-hydroxy-L-nicotine oxidase
000094652 650_2 $$2MeSH$$aArthrobacter: enzymology
000094652 650_2 $$2MeSH$$aBacterial Proteins: chemistry
000094652 650_2 $$2MeSH$$aCatalytic Domain
000094652 650_2 $$2MeSH$$aCrystallography, X-Ray
000094652 650_2 $$2MeSH$$aKinetics
000094652 650_2 $$2MeSH$$aMonoamine Oxidase: chemistry
000094652 650_2 $$2MeSH$$aNicotine: chemistry
000094652 650_2 $$2MeSH$$aOxidation-Reduction
000094652 650_2 $$2MeSH$$aOxidoreductases Acting on CH-NH Group Donors: chemistry
000094652 650_2 $$2MeSH$$aStructure-Activity Relationship
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000094652 7001_ $$aDecker, K.
000094652 7001_ $$aHolt, A.
000094652 7001_ $$aBartunik, H. D.
000094652 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.1016684108$$gVol. 108, p. 4800-4805$$p4800-4805$$q108<4800-4805$$tProceedings of the National Academy of Sciences of the United States of America$$v108$$x1091-6490$$y2011
000094652 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064382
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