2xlu › Citations

Joint functions of protein residues and NADP(H) in oxygen activation by flavin-containing monooxygenase.

Orru R, Pazmiño DE, Fraaije MW, Mattevi A
J Biol Chem 285 35021-8 (2010)
Related entries: 2xlp, 2xlr, 2xls, 2xlt

Cited: 31 times
EuropePMC logo PMID: 20807767

Abstract

The reactivity of flavoenzymes with dioxygen is at the heart of a number of biochemical reactions with far reaching implications for cell physiology and pathology. Flavin-containing monooxygenases are an attractive model system to study flavin-mediated oxygenation. In these enzymes, the NADP(H) cofactor is essential for stabilizing the flavin intermediate, which activates dioxygen and makes it ready to react with the substrate undergoing oxygenation. Our studies combine site-directed mutagenesis with the usage of NADP(+) analogues to dissect the specific roles of the cofactors and surrounding protein matrix. The highlight of this "double-engineering" approach is that subtle alterations in the hydrogen bonding and stereochemical environment can drastically alter the efficiency and outcome of the reaction with oxygen. This is illustrated by the seemingly marginal replacement of an Asn to Ser in the oxygen-reacting site, which inactivates the enzyme by effectively converting it into an oxidase. These data rationalize the effect of mutations that cause enzyme deficiency in patients affected by the fish odor syndrome. A crucial role of NADP(+) in the oxygenation reaction is to shield the reacting flavin N5 atom by H-bond interactions. A Tyr residue functions as backdoor that stabilizes this crucial binding conformation of the nicotinamide cofactor. A general concept emerging from this analysis is that the two alternative pathways of flavoprotein-oxygen reactivity (oxidation versus monooxygenation) are predicted to have very similar activation barriers. The necessity of fine tuning the hydrogen-bonding, electrostatics, and accessibility of the flavin will represent a challenge for the design and development of oxidases and monoxygenases for biotechnological applications.

Articles - 2xlu mentioned but not cited (1)

  1. Joint functions of protein residues and NADP(H) in oxygen activation by flavin-containing monooxygenase. Orru R, Pazmiño DE, Fraaije MW, Mattevi A. J Biol Chem 285 35021-35028 (2010)


Reviews citing this publication (3)

  1. Heteroatom-Heteroatom Bond Formation in Natural Product Biosynthesis. Waldman AJ, Ng TL, Wang P, Balskus EP. Chem Rev 117 5784-5863 (2017)
  2. Mechanistic and structural studies of the N-hydroxylating flavoprotein monooxygenases. Olucha J, Lamb AL. Bioorg Chem 39 171-177 (2011)
  3. MICAL, the flavoenzyme participating in cytoskeleton dynamics. Vanoni MA, Vitali T, Zucchini D. Int J Mol Sci 14 6920-6959 (2013)

Articles citing this publication (27)

  1. Snapshots of enzymatic Baeyer-Villiger catalysis: oxygen activation and intermediate stabilization. Orru R, Dudek HM, Martinoli C, Torres Pazmiño DE, Royant A, Weik M, Fraaije MW, Mattevi A. J Biol Chem 286 29284-29291 (2011)
  2. The substrate-bound crystal structure of a Baeyer-Villiger monooxygenase exhibits a Criegee-like conformation. Yachnin BJ, Sprules T, McEvoy MB, Lau PC, Berghuis AM. J Am Chem Soc 134 7788-7795 (2012)
  3. Two structures of an N-hydroxylating flavoprotein monooxygenase: ornithine hydroxylase from Pseudomonas aeruginosa. Olucha J, Meneely KM, Chilton AS, Lamb AL. J Biol Chem 286 31789-31798 (2011)
  4. Stabilization of C4a-hydroperoxyflavin in a two-component flavin-dependent monooxygenase is achieved through interactions at flavin N5 and C4a atoms. Thotsaporn K, Chenprakhon P, Sucharitakul J, Mattevi A, Chaiyen P. J Biol Chem 286 28170-28180 (2011)
  5. Exploring the biocatalytic scope of a bacterial flavin-containing monooxygenase. Rioz-Martínez A, Kopacz M, de Gonzalo G, Torres Pazmiño DE, Gotor V, Fraaije MW. Org Biomol Chem 9 1337-1341 (2011)
  6. Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs. Nicoll CR, Bailleul G, Fiorentini F, Mascotti ML, Fraaije MW, Mattevi A. Nat Struct Mol Biol 27 14-24 (2020)
  7. A flavoprotein monooxygenase that catalyses a Baeyer-Villiger reaction and thioether oxidation using NADH as the nicotinamide cofactor. Jensen CN, Cartwright J, Ward J, Hart S, Turkenburg JP, Ali ST, Allen MJ, Grogan G. Chembiochem 13 872-878 (2012)
  8. The Origin and Evolution of Baeyer-Villiger Monooxygenases (BVMOs): An Ancestral Family of Flavin Monooxygenases. Mascotti ML, Lapadula WJ, Juri Ayub M. PLoS One 10 e0132689 (2015)
  9. Hydrogen peroxide elimination from C4a-hydroperoxyflavin in a flavoprotein oxidase occurs through a single proton transfer from flavin N5 to a peroxide leaving group. Sucharitakul J, Wongnate T, Chaiyen P. J Biol Chem 286 16900-16909 (2011)
  10. Structural mechanism for bacterial oxidation of oceanic trimethylamine into trimethylamine N-oxide. Li CY, Chen XL, Zhang D, Wang P, Sheng Q, Peng M, Xie BB, Qin QL, Li PY, Zhang XY, Su HN, Song XY, Shi M, Zhou BC, Xun LY, Chen Y, Zhang YZ. Mol Microbiol 103 992-1003 (2017)
  11. Mechanistic studies on the flavin-dependent N⁶-lysine monooxygenase MbsG reveal an unusual control for catalysis. Robinson RM, Rodriguez PJ, Sobrado P. Arch Biochem Biophys 550-551 58-66 (2014)
  12. Role of Ser-257 in the sliding mechanism of NADP(H) in the reaction catalyzed by the Aspergillus fumigatus flavin-dependent ornithine N5-monooxygenase SidA. Shirey C, Badieyan S, Sobrado P. J Biol Chem 288 32440-32448 (2013)
  13. Human flavin-containing monooxygenase 3: Structural mapping of gene polymorphisms and insights into molecular basis of drug binding. Gao C, Catucci G, Di Nardo G, Gilardi G, Sadeghi SJ. Gene 593 91-99 (2016)
  14. Inactivation mechanism of N61S mutant of human FMO3 towards trimethylamine. Gao C, Catucci G, Castrignanò S, Gilardi G, Sadeghi SJ. Sci Rep 7 14668 (2017)
  15. Contribution to catalysis of ornithine binding residues in ornithine N5-monooxygenase. Robinson R, Qureshi IA, Klancher CA, Rodriguez PJ, Tanner JJ, Sobrado P. Arch Biochem Biophys 585 25-31 (2015)
  16. Mutations of an NAD(P)H-dependent flavoprotein monooxygenase that influence cofactor promiscuity and enantioselectivity. Jensen CN, Ali ST, Allen MJ, Grogan G. FEBS Open Bio 3 473-478 (2013)
  17. Exploring nicotinamide cofactor promiscuity in NAD(P)H-dependent flavin containing monooxygenases (FMOs) using natural variation within the phosphate binding loop. Structure and activity of FMOs from Cellvibrio sp. BR and Pseudomonas stutzeri NF13. Jensen CN, Ali ST, Allen MJ, Grogan G. J Mol Catal B Enzym 109 191-198 (2014)
  18. Structure-Based Redesign of a Self-Sufficient Flavin-Containing Monooxygenase towards Indigo Production. Lončar N, van Beek HL, Fraaije MW. Int J Mol Sci 20 E6148 (2019)
  19. How pH modulates the reactivity and selectivity of a siderophore-associated flavin monooxygenase. Frederick RE, Ojha S, Lamb A, Dubois JL. Biochemistry 53 2007-2016 (2014)
  20. Flavin oxidation in flavin-dependent N-monooxygenases. Robinson RM, Klancher CA, Rodriguez PJ, Sobrado P. Protein Sci 28 90-99 (2019)
  21. Use of Flavin-Containing Monooxygenases for Conversion of Trimethylamine in Salmon Protein Hydrolysates. Goris M, Puntervoll P, Rojo D, Claussen J, Larsen Ø, Garcia-Moyano A, Almendral D, Barbas C, Ferrer M, Bjerga GEK. Appl Environ Microbiol 86 e02105-20 (2020)
  22. Beyond the Protein Matrix: Probing Cofactor Variants in a Baeyer-Villiger Oxygenation Reaction. Martinoli C, Dudek HM, Orru R, Edmondson DE, Fraaije MW, Mattevi A. ACS Catal 3 3058-3062 (2013)
  23. Structural and Mechanistic Insights Into Dimethylsulfoxide Formation Through Dimethylsulfide Oxidation. Wang XJ, Zhang N, Teng ZJ, Wang P, Zhang WP, Chen XL, Zhang YZ, Chen Y, Fu HH, Li CY. Front Microbiol 12 735793 (2021)
  24. Evolution of enzyme functionality in the flavin-containing monooxygenases. Bailleul G, Yang G, Nicoll CR, Mattevi A, Fraaije MW, Mascotti ML. Nat Commun 14 1042 (2023)
  25. Tryptophan-47 in the active site of Methylophaga sp. strain SK1 flavin-monooxygenase is important for hydride transfer. Han A, Robinson RM, Badieyan S, Ellerbrock J, Sobrado P. Arch Biochem Biophys 532 46-53 (2013)
  26. A biosynthetic aspartate N-hydroxylase performs successive oxidations by holding intermediates at a site away from the catalytic center. Rotilio L, Boverio A, Nguyen QT, Mannucci B, Fraaije MW, Mattevi A. J Biol Chem 299 104904 (2023)
  27. Investigating the biochemical signatures and physiological roles of the FMO family using molecular phylogeny. Nicoll CR, Mascotti ML. BBA Adv 4 100108 (2023)


Quick links