mixed function oxygenases


Summary: Widely distributed enzymes that carry out oxidation-reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. They are also known as monooxygenases or hydroxylases. These reactions require two substrates as reductants for each of the two oxygen atoms. There are different classes of monooxygenases depending on the type of hydrogen-providing cosubstrate (COENZYMES) required in the mixed-function oxidation.

Top Publications

  1. Franceschini S, Fedkenheuer M, Vogelaar N, Robinson H, Sobrado P, Mattevi A. Structural insight into the mechanism of oxygen activation and substrate selectivity of flavin-dependent N-hydroxylating monooxygenases. Biochemistry. 2012;51:7043-5 pubmed
    ..The structural elucidation of the enzyme in complex with arginine provides insight into the role of electrostatics and hydrogen bonding in the mechanism of oxygen activation in this family of enzymes...
  2. McMurray F, Church C, Larder R, Nicholson G, Wells S, Teboul L, et al. Adult onset global loss of the fto gene alters body composition and metabolism in the mouse. PLoS Genet. 2013;9:e1003166 pubmed publisher
    ..Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake. ..
  3. Teufel R, Miyanaga A, Michaudel Q, Stull F, Louie G, Noel J, et al. Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement. Nature. 2013;503:552-556 pubmed publisher
    ..This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization. ..
  4. Teng F, Zhai L, Liu R, Bai W, Wang L, Huo D, et al. ZmGA3ox2, a candidate gene for a major QTL, qPH3.1, for plant height in maize. Plant J. 2013;73:405-16 pubmed publisher
    ..The successfully isolated qPH3.1 enriches our knowledge on the genetic basis of plant height in maize, and provides an opportunity for improvement of plant architecture in maize breeding...
  5. Wu M, Beckham G, Larsson A, Ishida T, Kim S, Payne C, et al. Crystal structure and computational characterization of the lytic polysaccharide monooxygenase GH61D from the Basidiomycota fungus Phanerochaete chrysosporium. J Biol Chem. 2013;288:12828-39 pubmed publisher
    ..A calculated potential energy surface for surface translation indicates that P. chrysosporium GH61D exhibits energy wells whose spacing seems adapted to the spacing of cellobiose units along a cellulose chain...
  6. Lutz A, Li P, Estrada J, Sidner R, Chihara R, Downey S, et al. Double knockout pigs deficient in N-glycolylneuraminic acid and galactose ?-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation. 2013;20:27-35 pubmed publisher
    ..This technology will accelerate the development of pigs for xenotransplantation research. ..
  7. Ge W, Wolf A, Feng T, Ho C, Sekirnik R, Zayer A, et al. Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. Nat Chem Biol. 2012;8:960-962 pubmed publisher
    ..This work reveals new therapeutic possibilities via oxygenase inhibition and by targeting modified over unmodified ribosomes. ..
  8. Hemsworth G, Henrissat B, Davies G, Walton P. Discovery and characterization of a new family of lytic polysaccharide monooxygenases. Nat Chem Biol. 2014;10:122-6 pubmed publisher
    ..The newly characterized AA11 family expands the LPMO clan, potentially broadening both the range of potential substrates and the types of reactive copper-oxygen species formed at the active site of LPMOs. ..
  9. Huijbers M, Montersino S, Westphal A, Tischler D, van Berkel W. Flavin dependent monooxygenases. Arch Biochem Biophys. 2014;544:2-17 pubmed publisher
    ..In this review we present an update of the classification of flavin-dependent monooxygenases and summarize the latest advances in our understanding of their catalytic and structural properties. ..

More Information


  1. Osborne R, Zhu H, Iavarone A, Blackburn N, Klinman J. Interdomain long-range electron transfer becomes rate-limiting in the Y216A variant of tyramine ?-monooxygenase. Biochemistry. 2013;52:1179-91 pubmed publisher
    ..These studies uncover a rate-limiting ET within the solvent-filled interface and lead to a paradigm shift in our understanding of the mononuclear dicopper monooxygenases...
  2. Ishiuchi K, Nakazawa T, Yagishita F, Mino T, Noguchi H, Hotta K, et al. Combinatorial generation of complexity by redox enzymes in the chaetoglobosin A biosynthesis. J Am Chem Soc. 2013;135:7371-7 pubmed publisher
    ..Our approach should expedite elucidation of pathways for other natural products biosynthesized by many uncharacterized enzymes of this fungus. ..
  3. Nguyen L, Cavadas M, Scholz C, Fitzpatrick S, Bruning U, Cummins E, et al. A dynamic model of the hypoxia-inducible factor 1? (HIF-1?) network. J Cell Sci. 2013;126:1454-63 pubmed publisher
  4. Scholz C, Cavadas M, Tambuwala M, Hams E, Rodriguez J, von Kriegsheim A, et al. Regulation of IL-1?-induced NF-?B by hydroxylases links key hypoxic and inflammatory signaling pathways. Proc Natl Acad Sci U S A. 2013;110:18490-5 pubmed publisher
    ..Thus, we hypothesize that hydroxylases regulate IL-1? signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1?-dependent inflammatory signaling. ..
  5. Cao L, Huang X, Chen C, Chen S. A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: a case report with literature review. J Neurol Sci. 2013;329:1-5 pubmed publisher
    ..In this study we identified the first SPG 35 family in Han population. Triple FA2H mutations seem to result in a severe phenotype while more patients are needed to establish the genotype-phenotype correlations. ..
  6. Kline C, Mayfield M, Blackburn N. HHM motif at the CuH-site of peptidylglycine monooxygenase is a pH-dependent conformational switch. Biochemistry. 2013;52:2586-96 pubmed publisher
    ..The data suggest a more general utility for the HHM motif as a copper- and pH-dependent conformational switch. ..
  7. Bey M, Zhou S, Poidevin L, Henrissat B, Coutinho P, Berrin J, et al. Cello-oligosaccharide oxidation reveals differences between two lytic polysaccharide monooxygenases (family GH61) from Podospora anserina. Appl Environ Microbiol. 2013;79:488-96 pubmed publisher
    ..The different properties of PaGH61A and PaGH61B and their effect on the interaction with CDH are discussed in regard to the proposed in vivo function of the CDH/GH61 enzyme system in oxidative cellulose hydrolysis...
  8. Bauman A, Broers B, Kline C, Blackburn N. A copper-methionine interaction controls the pH-dependent activation of peptidylglycine monooxygenase. Biochemistry. 2011;50:10819-28 pubmed publisher
    ..A model is presented in which H108 is protonated with a pK(a) of 4.6 to generate the inactive low-pH form with Cu(H) coordinated by M109, H107, and H172. ..
  9. Plackett A, Powers S, Fernandez Garcia N, Urbanová T, Takebayashi Y, Seo M, et al. Analysis of the developmental roles of the Arabidopsis gibberellin 20-oxidases demonstrates that GA20ox1, -2, and -3 are the dominant paralogs. Plant Cell. 2012;24:941-60 pubmed publisher
    ..Some phenotypic recovery of late flowers in GA-deficient mutants, including ga1-3, indicated the involvement of non-GA pathways in floral development. ..
  10. Noma A, Ishitani R, Kato M, Nagao A, Nureki O, Suzuki T. Expanding role of the jumonji C domain as an RNA hydroxylase. J Biol Chem. 2010;285:34503-7 pubmed publisher
    ..The finding provides an insight into the expanding role of JmjC protein as an RNA hydroxylase. ..
  11. Limdi N, Limdi M, Cavallari L, Anderson A, Crowley M, Baird M, et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis. 2010;56:823-31 pubmed publisher
    ..001). No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin). Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements. ..
  12. Park J, Park M, Kwon D, Kang M, Oh M, Han J, et al. Alpha 1,3-galactosyltransferase deficiency in pigs increases sialyltransferase activities that potentially raise non-gal xenoantigenicity. J Biomed Biotechnol. 2011;2011:560850 pubmed publisher
    ..This indicates that Neu5Gc may be a critical xenoantigen. The deletion of the CMAH gene in the GalT KO background is expected to further prolong xenograft survival. ..
  13. Kim Y, Kwon T, Yang H, Kim W, Youn H, Lee J, et al. Gene engineering, purification, crystallization and preliminary X-ray diffraction of cytochrome P450 p-coumarate-3-hydroxylase (C3H), the Arabidopsis membrane protein. Protein Expr Purif. 2011;79:149-55 pubmed publisher
  14. Li D, Delaney J, Page C, Yang X, Chen A, Wong C, et al. Exocyclic carbons adjacent to the N6 of adenine are targets for oxidation by the Escherichia coli adaptive response protein AlkB. J Am Chem Soc. 2012;134:8896-901 pubmed publisher
    ..The observation that AlkB can demethylate m6A in vitro suggests a role for AlkB in regulation of important cellular functions in vivo. ..
  15. Grigoriev I, Yu K, Martinez Sanchez E, Serra Marques A, Smal I, Meijering E, et al. Rab6, Rab8, and MICAL3 cooperate in controlling docking and fusion of exocytotic carriers. Curr Biol. 2011;21:967-74 pubmed publisher
    ..Taken together, the results of our study illustrate cooperation of two Rab proteins in constitutive exocytosis and implicates a redox enzyme in this process. ..
  16. Bell T, Yergeau E, Martineau C, Juck D, Whyte L, Greer C. Identification of nitrogen-incorporating bacteria in petroleum-contaminated arctic soils by using [15N]DNA-based stable isotope probing and pyrosequencing. Appl Environ Microbiol. 2011;77:4163-71 pubmed publisher
    ..A better understanding of how groups of hydrocarbon-degraders contribute to the catabolism of petroleum will facilitate the design of more targeted bioremediation treatments. ..
  17. Celestino Soper P, Shaw C, Sanders S, Li J, Murtha M, Ercan Sencicek A, et al. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet. 2011;20:4360-70 pubmed publisher
    ..gov/geo/, date last accessed on 30 August 2011). Genboree accession: http://genboree.org/java-bin/gbrowser.jsp?refSeqId=1868&entryPointId=chr17&from=53496072&to=53694382&isPublic=yes, date last accessed on 30 August 2011. ..
  18. Qiao K, Chooi Y, Tang Y. Identification and engineering of the cytochalasin gene cluster from Aspergillus clavatus NRRL 1. Metab Eng. 2011;13:723-32 pubmed publisher
    ..Our results not only shed light on the biosynthesis of cytochalasins, but also provided genetic tools for increasing and engineering the production. ..
  19. Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, et al. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature. 2010;468:330-3 pubmed publisher
    ..This study also depicts a general mechanistic view of how a methyl group is oxidatively removed from different biological substrates. ..
  20. Thotsaporn K, Chenprakhon P, Sucharitakul J, Mattevi A, Chaiyen P. Stabilization of C4a-hydroperoxyflavin in a two-component flavin-dependent monooxygenase is achieved through interactions at flavin N5 and C4a atoms. J Biol Chem. 2011;286:28170-80 pubmed publisher
  21. Church C, Moir L, McMurray F, Girard C, Banks G, Teboul L, et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010;42:1086-92 pubmed publisher
    ..Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice. ..
  22. Kruer M, Paisan Ruiz C, Boddaert N, Yoon M, Hama H, Gregory A, et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010;68:611-8 pubmed publisher
    ..These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA. ..
  23. Loenarz C, Schofield C. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem Sci. 2011;36:7-18 pubmed publisher
    ..The combination of new molecular biological and analytical techniques is likely to reveal further roles for oxygenase-mediated modifications to biomacromolecules. ..
  24. Tatonetti N, Dudley J, Sagreiya H, Butte A, Altman R. An integrative method for scoring candidate genes from association studies: application to warfarin dosing. BMC Bioinformatics. 2010;11 Suppl 9:S9 pubmed publisher
    ..886) and high-dose (AUROC=0.764) responders. Our method offers a new route for candidate pharmacogene discovery from pharmacogenomics GWAS, and serves as a foundation for future work in methods for predictive pharmacogenomics. ..
  25. Moreau C, Bajolle F, Siguret V, Lasne D, Golmard J, Elie C, et al. Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood. 2012;119:861-7 pubmed publisher
    ..7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated. ..
  26. Pierson T, Simeonov D, Sincan M, Adams D, Markello T, Golas G, et al. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Eur J Hum Genet. 2012;20:476-9 pubmed publisher
    ..The presence of a sural nerve axonal neuropathy had not been previously associated with this disorder and so may extend the phenotype. ..
  27. Bulleid N, Ellgaard L. Multiple ways to make disulfides. Trends Biochem Sci. 2011;36:485-92 pubmed publisher
    ..Here we discuss these various pathways for disulfide formation in the mammalian ER and highlight the central role played by glutathione in regulating this process...
  28. Mielecki D, Zugaj D, Muszewska A, Piwowarski J, Chojnacka A, Mielecki M, et al. Novel AlkB dioxygenases--alternative models for in silico and in vivo studies. PLoS ONE. 2012;7:e30588 pubmed publisher
  29. Ramirez A, Shi Y, Schildcrout J, Delaney J, Xu H, Oetjens M, et al. Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenomics. 2012;13:407-18 pubmed publisher
    ..Implementing these predictions via dispensable pill regimens similarly reduced dosing error. These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery. ..
  30. Olucha J, Meneely K, Chilton A, Lamb A. Two structures of an N-hydroxylating flavoprotein monooxygenase: ornithine hydroxylase from Pseudomonas aeruginosa. J Biol Chem. 2011;286:31789-98 pubmed publisher
  31. Chaiyen P, Fraaije M, Mattevi A. The enigmatic reaction of flavins with oxygen. Trends Biochem Sci. 2012;37:373-80 pubmed publisher
    ..A challenge for the future will be to use these emerging concepts to rationally engineer flavoenzymes, paving the way to new research avenues with far-reaching implications for oxidative biocatalysis and metabolic engineering. ..
  32. Du H, Wang N, Cui F, Li X, Xiao J, Xiong L. Characterization of the beta-carotene hydroxylase gene DSM2 conferring drought and oxidative stress resistance by increasing xanthophylls and abscisic acid synthesis in rice. Plant Physiol. 2010;154:1304-18 pubmed publisher
    ..We conclude that the DSM2 gene significantly contributes to control of the xanthophyll cycle and ABA synthesis, both of which play critical roles in the establishment of drought resistance in rice. ..
  33. Celestino Soper P, Violante S, Crawford E, Luo R, Lionel A, Delaby E, et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012;109:7974-81 pubmed publisher
  34. de Gonzalo G, Mihovilovic M, Fraaije M. Recent developments in the application of Baeyer-Villiger monooxygenases as biocatalysts. Chembiochem. 2010;11:2208-31 pubmed publisher
  35. McTaggart J, Lee S, Iberl M, Church C, Cox R, Ashcroft F. FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PLoS ONE. 2011;6:e27968 pubmed publisher
    ..The widespread expression of FTO in neurones also suggests that physiological studies of this protein should not be limited to the hypothalamus. ..
  36. Yang M, Chowdhury R, Ge W, Hamed R, McDonough M, Claridge T, et al. Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. FEBS J. 2011;278:1086-97 pubmed publisher
    ..NMR and crystallographic analyses show that the histidinyl hydroxylation occurs at the ?-position. The results further expand the scope of FIH-catalysed hydroxylations. ..
  37. Schelleman H, Brensinger C, Chen J, Finkelman B, Rieder M, Kimmel S. New genetic variant that might improve warfarin dose prediction in African Americans. Br J Clin Pharmacol. 2010;70:393-9 pubmed publisher
    ..Future studies with a larger sample size will be needed to confirm our findings. ..
  38. Tang H, Yao Y, Zhang D, Meng X, Wang L, Yu H, et al. A novel NADH-dependent and FAD-containing hydroxylase is crucial for nicotine degradation by Pseudomonas putida. J Biol Chem. 2011;286:39179-87 pubmed publisher
    ..This study demonstrates the importance of the newly discovered enzyme HspB, which is crucial for nicotine degradation by the Pseudomonas strain...
  39. Tavridou A, Petridis I, Vasileiadis M, Ragia G, Heliopoulos I, Vargemezis V, et al. Association of VKORC1 -1639 G>A polymorphism with carotid intima-media thickness in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2011;94:236-41 pubmed publisher
    ..We examined a potential association between VKORC1 -1639 G>A polymorphism and T2DM and, also, the association of this polymorphism with carotid intima-media thickness (cIMT)...
  40. Djaffar Jureidini I, Chamseddine N, Keleshian S, Naoufal R, Zahed L, Hakime N. Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population. Genet Test Mol Biomarkers. 2011;15:827-30 pubmed publisher
    ..Over 50% of the Lebanese population seem to be carrying more than two independent risk alleles, and is therefore potentially at high risk of over-anticoagulation. ..
  41. Cha P, Mushiroda T, Takahashi A, Kubo M, Minami S, Kamatani N, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet. 2010;19:4735-44 pubmed publisher
    ..Our study also implied that common SNPs other than those in the CYP2C9, VKORC1 and CYP4F2 genes that show strong effect on the therapeutic warfarin dose might not exist. ..
  42. Chocklett S, Sobrado P. Aspergillus fumigatus SidA is a highly specific ornithine hydroxylase with bound flavin cofactor. Biochemistry. 2010;49:6777-83 pubmed publisher
    ..NADP(+) is a competitive inhibitor with respect to NADPH, demonstrating that Af SidA forms a ternary complex with NADP(+) and l-ornithine during catalysis. The data suggest that Af SidA likely proceeds by a sequential kinetic mechanism. ..
  43. Watschinger K, Keller M, Golderer G, Hermann M, Maglione M, Sarg B, et al. Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes. Proc Natl Acad Sci U S A. 2010;107:13672-7 pubmed publisher
    ..This sequence assignment suggests that alkylglycerol monooxygenase forms a distinct third group among tetrahydrobiopterin-dependent enzymes. ..
  44. Watschinger K, Fuchs J, Yarov Yarovoy V, Keller M, Golderer G, Hermetter A, et al. Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase. Biochem J. 2012;443:279-86 pubmed publisher
    ..Prediction of a part of the structure using the Rosetta membrane ab initio method led to a plausible suggestion for a structure of the catalytic site of alkylglycerol mono-oxygenase. ..
  45. Dudek H, de Gonzalo G, Pazmiño D, Stepniak P, Wyrwicz L, Rychlewski L, et al. Mapping the substrate binding site of phenylacetone monooxygenase from Thermobifida fusca by mutational analysis. Appl Environ Microbiol. 2011;77:5730-8 pubmed publisher
    ..These findings will aid in more dedicated and effective redesign of PAMO and related monooxygenases toward an expanded substrate scope...
  46. Wu Q, Saunders R, Szkudlarek Mikho M, Serna I, Chin K. The obesity-associated Fto gene is a transcriptional coactivator. Biochem Biophys Res Commun. 2010;401:390-5 pubmed publisher
    ..How FTO reactivates transcription from methyl-repressed gene needs to be further investigated. ..
  47. El Sharkawy I, El Kayal W, Prasath D, Fernandez H, Bouzayen M, Svircev A, et al. Identification and genetic characterization of a gibberellin 2-oxidase gene that controls tree stature and reproductive growth in plum. J Exp Bot. 2012;63:1225-39 pubmed publisher
    ..The studies reveal the possibility of utilizing PslGA2ox as a marker for developing size-controlling rootstocks in Prunus. ..
  48. McCormick M, Lippard S. Analysis of substrate access to active sites in bacterial multicomponent monooxygenase hydroxylases: X-ray crystal structure of xenon-pressurized phenol hydroxylase from Pseudomonas sp. OX1. Biochemistry. 2011;50:11058-69 pubmed publisher
  49. Gong I, Tirona R, Schwarz U, Crown N, Dresser G, Larue S, et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. 2011;118:3163-71 pubmed publisher
    ..We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism. ..
  50. Rose N, McDonough M, King O, Kawamura A, Schofield C. Inhibition of 2-oxoglutarate dependent oxygenases. Chem Soc Rev. 2011;40:4364-97 pubmed publisher
    ..In this critical review, we describe studies on the inhibition of 2OG oxygenases, focusing on small molecules, and discuss the potential of 2OG oxygenases as therapeutic targets (295 references). ..
  51. Anderson J, Horne B, Stevens S, Woller S, Samuelson K, Mansfield J, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation. 2012;125:1997-2005 pubmed publisher
    ..The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862. ..
  52. Lee K, Maeng J, Choi J, Lee Y, Hwang C, Park S, et al. Role of Junctin protein interactions in cellular dynamics of calsequestrin polymer upon calcium perturbation. J Biol Chem. 2012;287:1679-87 pubmed publisher
    ..Accordingly, we conclude that reversible polymerization and depolymerization of CSQ are critical in SR Ca(2+) homeostasis. ..
  53. Shahin M, Khalifa S, Gong Y, Hammad L, Sallam M, El Shafey M, et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics. 2011;21:130-5 pubmed publisher
    ..The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry. ..