Home LiteratureArticle Details
PMID: 18813363 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Fe(II)/alpha-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism.

Dalton transactions (Cambridge, England : 2003) ·No. 38 ·2008-10-14 ·Pages 5132-42

Simmons JM, Müller TA, Hausinger RP

Abstract

Fe(II)/alpha-ketoglutarate-dependent hydroxylases uniformly possess a double-stranded beta-helix fold with two conserved histidines and one carboxylate coordinating their mononuclear ferrous ions. Oxidative decomposition of the alpha-keto acid is proposed to generate a ferryl-oxo intermediate capable of hydroxylating unactivated carbon atoms in a myriad of substrates. This Perspective focuses on a subgroup of these enzymes that are involved in pyrimidine salvage, purine decomposition, nucleoside and nucleotide hydroxylation, DNA/RNA repair, and chromatin modification. The varied reaction schemes are presented, and selected structural and kinetic information is summarized.

MeSH Terms
Animals Chromatin/metabolism Dioxygenases/metabolism Fungal Proteins/metabolism Humans Iron/metabolism Mixed Function Oxygenases/metabolism Models, Molecular Nucleosides/metabolism Nucleotides/metabolism Polynucleotides/metabolism
Chemicals
Chromatin Fungal Proteins Nucleosides Nucleotides Polynucleotides Iron Mixed Function Oxygenases Dioxygenases xanthine dioxygenase, Aspergillus nidulans thymine, 2-oxoglutarate dioxygenase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Simmons Jana M
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA.
Müller Tina A
Hausinger Robert P
References (98)
98 references, click to expand
  1. Tandemly repeated DNA is a target for the partial replacement of thymine by beta-D-glucosyl-hydroxymethyluracil in Trypanosoma brucei.
    Mol Biochem Parasitol. 2000 Jul;109(2):133-45 PMID: 10960172
  2. Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB.
    BMC Genomics. 2003 Dec 10;4(1):48 PMID: 14667252
  3. Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins.
    J Inorg Biochem. 2006 Apr;100(4):644-69 PMID: 16513174
  4. A non-heme iron protein with heme tendencies: an investigation of the substrate specificity of thymine hydroxylase.
    Biochemistry. 1993 Dec 21;32(50):14023-33 PMID: 8268181
  5. Oxygenases involved in thymine and thymidine metabolism in Neurospora crassa.
    FEBS Lett. 1972 Mar 15;21(2):135-138 PMID: 11946494
  6. Histone demethylation by a family of JmjC domain-containing proteins.
    Nature. 2006 Feb 16;439(7078):811-6 PMID: 16362057
  7. Kinetic studies of Escherichia coli AlkB using a new fluorescence-based assay for DNA demethylation.
    Nucleic Acids Res. 2007;35(21):e147 PMID: 18003660
  8. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily.
    BMC Biochem. 2007;8:23 PMID: 17996046
  9. Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway.
    Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15351-6 PMID: 12432100
  10. A new gene (alkB) of Escherichia coli that controls sensitivity to methyl methane sulfonate.
    J Bacteriol. 1983 Mar;153(3):1301-7 PMID: 6337994
  11. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues.
    J Biol Chem. 2005 Nov 25;280(47):39448-59 PMID: 16174769
  12. Expression of the human DNA glycosylase hSMUG1 in Trypanosoma brucei causes DNA damage and interferes with J biosynthesis.
    Nucleic Acids Res. 2002 Sep 15;30(18):3919-26 PMID: 12235375
  13. Demethylation of 3-methylthymine in DNA by bacterial and human DNA dioxygenases.
    J Biol Chem. 2004 Sep 24;279(39):40470-4 PMID: 15269201
  14. Tetrahydropterin-dependent amino acid hydroxylases.
    Annu Rev Biochem. 1999;68:355-81 PMID: 10872454
  15. The 2-His-1-carboxylate facial triad: a versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes.
    J Biol Inorg Chem. 2005 Mar;10(2):87-93 PMID: 15739104
  16. AlkB restores the biological function of mRNA and tRNA inactivated by chemical methylation.
    Mol Cell. 2004 Oct 8;16(1):107-16 PMID: 15469826
  17. Signalling hypoxia by HIF hydroxylases.
    Biochem Biophys Res Commun. 2005 Dec 9;338(1):617-26 PMID: 16139242
  18. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA.
    Nature. 2008 Apr 24;452(7190):961-5 PMID: 18432238
  19. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau.
    J Biol Chem. 2003 Feb 28;278(9):7558-63 PMID: 12482756
  20. Spectroscopic evidence for a high-spin Br-Fe(IV)-oxo intermediate in the alpha-ketoglutarate-dependent halogenase CytC3 from Streptomyces.
    J Am Chem Soc. 2007 Nov 7;129(44):13408-9 PMID: 17939667
  21. Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.
    Nat Struct Mol Biol. 2007 Aug;14(8):689-95 PMID: 17589523
  22. J-binding protein increases the level and retention of the unusual base J in trypanosome DNA.
    Mol Microbiol. 2002 Oct;46(1):37-47 PMID: 12366829
  23. Structural insights into histone demethylation by JMJD2 family members.
    Cell. 2006 May 19;125(4):691-702 PMID: 16677698
  24. Studies on the lysyl hydroxylase reaction. I. Initial velocity kinetics and related aspects.
    Biochim Biophys Acta. 1980 Jan 11;611(1):40-50 PMID: 6766066
  25. JBP2, a SWI2/SNF2-like protein, regulates de novo telomeric DNA glycosylation in bloodstream form Trypanosoma brucei.
    Mol Biochem Parasitol. 2007 Nov;156(1):24-31 PMID: 17706299
  26. Heme-Containing Oxygenases.
    Chem Rev. 1996 Nov 7;96(7):2841-2888 PMID: 11848843
  27. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.
    Nature. 2002 Sep 12;419(6903):174-8 PMID: 12226667
  28. Genes of the thymidine salvage pathway: thymine-7-hydroxylase from a Rhodotorula glutinis cDNA library and iso-orotate decarboxylase from Neurospora crassa.
    Biochim Biophys Acta. 2005 May 25;1723(1-3):256-64 PMID: 15794921
  29. Reversal of DNA alkylation damage by two human dioxygenases.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16660-5 PMID: 12486230
  30. Evidence for an alternative pathway of xanthine oxidation in Aspergillus nidulans.
    Biochim Biophys Acta. 1968 Sep 24;166(2):569-71 PMID: 5680611
  31. Enzymatic hydroxylation of aromatic compounds.
    Cell Mol Life Sci. 2007 Feb;64(3):271-93 PMID: 17221166
  32. Structural basis of the recognition of a methylated histone tail by JMJD2A.
    Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10818-23 PMID: 17567753
  33. The identification of hydroxymethyluracil in DNA of Trypanosoma brucei.
    Nucleic Acids Res. 1993 May 11;21(9):2039-43 PMID: 8502544
  34. Dioxygenases as O2-dependent regulators of the hypoxic response pathway.
    Biochem Biophys Res Commun. 2005 Dec 9;338(1):639-47 PMID: 16140259
  35. Identification of two alpha-ketoglutarate-dependent dioxygenases in extracts of Rhodotorula glutinis catalyzing deoxyuridine hydroxylation.
    J Biol Chem. 1985 Aug 25;260(18):9972-5 PMID: 4040518
  36. JMJD6 is a histone arginine demethylase.
    Science. 2007 Oct 19;318(5849):444-7 PMID: 17947579
  37. Substrate specificities of bacterial and human AlkB proteins.
    Nucleic Acids Res. 2004;32(11):3456-61 PMID: 15229293
  38. Mechanism-based inactivation of thymine hydroxylase, an alpha-ketoglutarate-dependent dioxygenase, by 5-ethynyluracil.
    Biochemistry. 1993 Dec 21;32(50):14034-42 PMID: 8268182
  39. Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.
    Nature. 2007 Jul 5;448(7149):87-91 PMID: 17589501
  40. The 2-His-1-carboxylate facial triad--an emerging structural motif in mononuclear non-heme iron(II) enzymes.
    Eur J Biochem. 1997 Dec 15;250(3):625-9 PMID: 9461283
  41. The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase.
    Nucleic Acids Res. 2007;35(7):2107-15 PMID: 17389644
  42. Characterization of active site variants of xanthine hydroxylase from Aspergillus nidulans.
    Arch Biochem Biophys. 2008 Feb 1;470(1):44-53 PMID: 18036331
  43. Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.
    Dev Dyn. 2008 Feb;237(2):316-27 PMID: 18163532
  44. Thymine 7-hydroxylase from Neurospora crassa. Substrate specificity studies.
    Biochim Biophys Acta. 1977 Apr 12;481(2):431-7 PMID: 139930
  45. Catalysis of three sequential dioxygenase reactions by thymine 7-hydroxylase.
    Arch Biochem Biophys. 1973 Nov;159(1):180-7 PMID: 4274083
  46. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha.
    J Biol Chem. 2003 Jan 17;278(3):1802-6 PMID: 12446723
  47. The cell-free conversion of a deoxyribonucleoside to a ribonucleoside without detachment of the deoxyribose.
    Biochem Biophys Res Commun. 1968 Dec 9;33(5):806-11 PMID: 5723341
  48. Herbicide-degrading alpha-keto acid-dependent enzyme TfdA: metal coordination environment and mechanistic insights.
    Biochemistry. 1999 Dec 14;38(50):16714-26 PMID: 10600135
  49. Biosynthesis and function of the modified DNA base beta-D-glucosyl-hydroxymethyluracil in Trypanosoma brucei.
    Mol Cell Biol. 1998 Oct;18(10):5643-51 PMID: 9742081
  50. A stereochemical concept for the catalytic mechanism of prolylhydroxylase: applicability to classification and design of inhibitors.
    J Theor Biol. 1982 Jan 21;94(2):421-55 PMID: 6281585
  51. beta-D-glucosyl-hydroxymethyluracil is a conserved DNA modification in kinetoplastid protozoans and is abundant in their telomeres.
    Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2366-71 PMID: 9482891
  52. Substrate trafficking and dioxygen activation in bacterial multicomponent monooxygenases.
    Acc Chem Res. 2007 Jul;40(7):466-74 PMID: 17518435
  53. Thymine 7-hydroxylase and pyrimidine deoxyribonucleoside 2' -hydroxylase activities in Rhodotorula glutinis.
    J Biol Chem. 1978 Sep 25;253(18):6511-5 PMID: 567220
  54. Base J, found in nuclear DNA of Trypanosoma brucei, is not a target for DNA glycosylases.
    DNA Repair (Amst). 2004 Feb 3;3(2):145-54 PMID: 14706348
  55. EXAFS spectroscopic evidence for an Fe=O unit in the Fe(IV) intermediate observed during oxygen activation by taurine:alpha-ketoglutarate dioxygenase.
    J Am Chem Soc. 2004 Jul 7;126(26):8108-9 PMID: 15225039
  56. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts.
    J Biotechnol. 2006 Aug 5;124(4):670-89 PMID: 16712999
  57. beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei.
    Cell. 1993 Dec 17;75(6):1129-36 PMID: 8261512
  58. AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo.
    Nat Struct Mol Biol. 2005 Oct;12(10):855-60 PMID: 16200073
  59. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli.
    Nature. 2002 Sep 12;419(6903):178-82 PMID: 12226668
  60. Minimal methylated substrate and extended substrate range of Escherichia coli AlkB protein, a 1-methyladenine-DNA dioxygenase.
    J Biol Chem. 2003 Nov 7;278(45):44348-54 PMID: 12944387
  61. The first direct characterization of a high-valent iron intermediate in the reaction of an alpha-ketoglutarate-dependent dioxygenase: a high-spin FeIV complex in taurine/alpha-ketoglutarate dioxygenase (TauD) from Escherichia coli.
    Biochemistry. 2003 Jun 24;42(24):7497-508 PMID: 12809506
  62. Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase.
    J Biol Chem. 1984 May 10;259(9):5403-5 PMID: 6325436
  63. 18-O studies of the 2-ketoglutarate-dependent sequential oxygenation of thymine to 5-carboxyuracil.
    J Biol Chem. 1971 May 25;246(10):3314-9 PMID: 5574400
  64. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.
    Cell. 2004 Dec 29;119(7):941-53 PMID: 15620353
  65. Markedly different ascorbate dependencies of the sequential alpha-ketoglutarate dioxygenase reactions catalyzed by an essentially homogeneous thymine 7-hydroxylase from Rhodotorula glutinis.
    J Biol Chem. 1983 Sep 10;258(17):10551-7 PMID: 6684117
  66. Stopped-flow kinetic analysis of Escherichia coli taurine/alpha-ketoglutarate dioxygenase: interactions with alpha-ketoglutarate, taurine, and oxygen.
    Biochemistry. 1999 Nov 16;38(46):15278-86 PMID: 10563813
  67. Direct detection of oxygen intermediates in the non-heme Fe enzyme taurine/alpha-ketoglutarate dioxygenase.
    J Am Chem Soc. 2004 Feb 4;126(4):1022-3 PMID: 14746461
  68. Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase.
    Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14738-43 PMID: 17003127
  69. Molybdenum-containing hydroxylases.
    Arch Biochem Biophys. 2005 Jan 1;433(1):107-16 PMID: 15581570
  70. Metabolism of pyrimidine deoxyribonucleosides in Neurospora crassa.
    J Bacteriol. 1975 Feb;121(2):648-55 PMID: 122971
  71. The modified base J is the target for a novel DNA-binding protein in kinetoplastid protozoans.
    EMBO J. 1999 Nov 15;18(22):6573-81 PMID: 10562569
  72. A kinetic study of thymine 7-hydroxylase from neurospora crassa.
    Biochemistry. 1975 Nov 4;14(22):4999-5003 PMID: 126696
  73. 7-Hydroxylation of thymine in a Neurospora strain coupled to oxidative decarboxylation of 2-ketoglutarate.
    Biochim Biophys Acta. 1970 Jul 15;212(1):50-7 PMID: 5500945
  74. Cofactor requirements of thymine 7-hydroxylase.
    Biochim Biophys Acta. 1967 Mar 15;132(2):525-8 PMID: 6031142
  75. The diverse and pervasive chemistries of the alpha-keto acid dependent enzymes.
    J Biol Inorg Chem. 2007 Jun;12(5):587-601 PMID: 17431691
  76. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage.
    EMBO J. 2006 Jul 26;25(14):3389-97 PMID: 16858410
  77. Regulation of trypanosome DNA glycosylation by a SWI2/SNF2-like protein.
    Mol Cell. 2005 Feb 4;17(3):441-51 PMID: 15694344
  78. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA.
    Nature. 2003 Feb 20;421(6925):859-63 PMID: 12594517
  79. Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA.
    EMBO J. 2006 May 17;25(10):2189-98 PMID: 16642038
  80. Expression and sub-cellular localization of human ABH family molecules.
    J Cell Mol Med. 2007 Sep-Oct;11(5):1105-16 PMID: 17979886
  81. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.
    Science. 2007 Nov 30;318(5855):1469-72 PMID: 17991826
  82. Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli.
    Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14051-6 PMID: 15381779
  83. Structure and expression of the alkB gene of Escherichia coli related to the repair of alkylated DNA.
    J Biol Chem. 1986 Nov 25;261(33):15772-7 PMID: 3536913
  84. Determination of intra- and intermolecular tritium isotope effects in the reaction of thymine 7-hydroxylase.
    Biochim Biophys Acta. 1982 Oct 5;707(2):259-66 PMID: 6215947
  85. Convergent evolution of hydroxylation mechanisms in the fungal kingdom: molybdenum cofactor-independent hydroxylation of xanthine via alpha-ketoglutarate-dependent dioxygenases.
    Mol Microbiol. 2005 Jul;57(1):276-90 PMID: 15948966
  86. Expanding chemical biology of 2-oxoglutarate oxygenases.
    Nat Chem Biol. 2008 Mar;4(3):152-6 PMID: 18277970
  87. The selectivity and inhibition of AlkB.
    J Biol Chem. 2003 Mar 21;278(12):10157-61 PMID: 12517755
  88. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.
    Nature. 2006 Feb 16;439(7078):879-84 PMID: 16482161
  89. Aberrant activity of the DNA repair enzyme AlkB.
    J Inorg Biochem. 2004 May;98(5):856-61 PMID: 15134932
  90. Uracil's uncoupling of the decarboxylation of alpha-ketoglutarate in the thymine 7-hydroxylase reaction of Neurospora crassa.
    J Biol Chem. 1981 Jun 25;256(12):6098-101 PMID: 6453866
  91. Separation and characterization of pyrimidine deoxyribonucleoside 2'-hydroxylase and thymine 7-hydroxylase from Aspergillus nidulans.
    Int J Biochem. 1984;16(4):429-34 PMID: 6370754
  92. Direct repair of the exocyclic DNA adduct 1,N6-ethenoadenine by the DNA repair AlkB proteins.
    J Am Chem Soc. 2005 Oct 26;127(42):14594-5 PMID: 16231911
  93. Multiple Rieske proteins in prokaryotes: where and why?
    Biochim Biophys Acta. 2005 Nov 15;1710(1):1-12 PMID: 16271700
  94. The central roles of telomeres and subtelomeres in antigenic variation in African trypanosomes.
    Chromosome Res. 2005;13(5):525-33 PMID: 16132817
  95. Purification and characterization of the FeII- and alpha-ketoglutarate-dependent xanthine hydroxylase from Aspergillus nidulans.
    Biochemistry. 2007 May 8;46(18):5293-304 PMID: 17429948
  96. Localization of the modified base J in telomeric VSG gene expression sites of Trypanosoma brucei.
    Genes Dev. 1997 Dec 1;11(23):3232-41 PMID: 9389654
  97. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).
    Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9 PMID: 16782814
  98. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes.
    Crit Rev Biochem Mol Biol. 2004 Jan-Feb;39(1):21-68 PMID: 15121720
Article Info
Journal
Dalton transactions (Cambridge, England : 2003)
Abbr.
Dalton Trans
ISSN
1477-9226
DOI
10.1039/b803512a
Published
2008-10-14
Epub
2008-00-27
Pages
5132-42
Language
English
Region
England
NLM ID
101176026
PMCID
PMC2907160
Subset
IM
Grants
NIGMS NIH HHS · R01 GM063584 · United States
NIGMS NIH HHS · R01 GM063584-01A1 · United States
NIGMS NIH HHS · GM 063584 · United States
External Links
PubMed source DOI: 10.1039/b803512a PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2