2toh Citations

Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site.

Biochemistry 37 13437-45 (1998)
Cited: 51 times
EuropePMC logo PMID: 9753429


TyrOH is a non-heme iron enzyme which uses molecular oxygen to hydroxylate tyrosine to form L-dihydroxyphenylalanine (L-DOPA), and tetrahydrobiopterin to form 4a-hydroxybiopterin, in the rate-limiting step of the catecholamine biosynthetic pathway. The 2.3 A crystal structure of the catalytic and tetramerization domains of rat tyrosine hydroxylase (TyrOH) in the presence of the cofactor analogue 7,8-dihydrobiopterin and iron shows the mode of pterin binding and the proximity of its hydroxylated 4a carbon to the required iron. The pterin binds on one face of the large active-site cleft, forming an aromatic pi-stacking interaction with Phe300. This phenylalanine residue of TyrOH is found to be hydroxylated in the meta position, most likely through an autocatalytic process, and to consequently form a hydrogen bond to the main-chain carbonyl of Gln310 which anchors Phe300 in the active site. The bound pterin forms hydrogen bonds from N-8 to the main-chain carbonyl of Leu295, from O-4 to Tyr371 and Glu376, from the C-1' OH to the main-chain amides of Leu294 and Leu295, and from the C-2' hydroxyl to an iron-coordinating water. The part of the pterin closest to the iron is the O-4 carbonyl oxygen at a distance of 3.6 A. The iron is 5.6 A from the pterin 4a carbon which is hydroxylated in the enzymatic reaction. No structural changes are observed between the pterin bound and the nonliganded enzyme. On the basis of these structures, molecular oxygen could bind in a bridging position optimally between the pterin C-4a and iron atom prior to substrate hydroxylation. This structure represents the first report of close interactions between pterin and iron in an enzyme active site.

Reviews - 2toh mentioned but not cited (1)

  1. Mechanism of aromatic amino acid hydroxylation. Fitzpatrick PF. Biochemistry 42 14083-14091 (2003)

Articles - 2toh mentioned but not cited (2)

  1. The solution structure of the regulatory domain of tyrosine hydroxylase. Zhang S, Huang T, Ilangovan U, Hinck AP, Fitzpatrick PF. J. Mol. Biol. 426 1483-1497 (2014)
  2. Structural and thermodynamic insight into phenylalanine hydroxylase from the human pathogen Legionella pneumophila. Leiros HK, Flydal MI, Martinez A. FEBS Open Bio 3 370-378 (2013)

Reviews citing this publication (11)

  1. Dioxygen activation by nonheme iron enzymes with the 2-His-1-carboxylate facial triad that generate high-valent oxoiron oxidants. Kal S, Que L. J. Biol. Inorg. Chem. 22 339-365 (2017)
  2. Understanding and applying tyrosine biochemical diversity. Jones LH, Narayanan A, Hett EC. Mol Biosyst 10 952-969 (2014)
  3. Complex molecular regulation of tyrosine hydroxylase. Tekin I, Roskoski R, Carkaci-Salli N, Vrana KE. J Neural Transm (Vienna) 121 1451-1481 (2014)
  4. 4-Hydroxyphenylpyruvate dioxygenase. Moran GR. Arch. Biochem. Biophys. 433 117-128 (2005)
  5. Biology and chemistry of the inhibition of nitric oxide synthases by pteridine-derivatives as therapeutic agents. Matter H, Kotsonis P. Med Res Rev 24 662-684 (2004)
  6. Non-heme iron oxygenases. Ryle MJ, Hausinger RP. Curr Opin Chem Biol 6 193-201 (2002)
  7. Catecholamine biosynthesis and physiological regulation in neuroendocrine cells. Flatmark T. Acta Physiol. Scand. 168 1-17 (2000)
  8. Combining structural genomics and enzymology: completing the picture in metabolic pathways and enzyme active sites. Erlandsen H, Abola EE, Stevens RC. Curr. Opin. Struct. Biol. 10 719-730 (2000)
  9. Design of high-throughput methods of protein production for structural biology. Stevens RC. Structure 8 R177-85 (2000)
  10. The structural basis of phenylketonuria. Erlandsen H, Stevens RC. Mol. Genet. Metab. 68 103-125 (1999)
  11. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Schofield CJ, Zhang Z. Curr. Opin. Struct. Biol. 9 722-731 (1999)

Articles citing this publication (37)

  1. Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Raman CS, Li H, Martásek P, Král V, Masters BS, Poulos TL. Cell 95 939-950 (1998)
  2. High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. Andersen OA, Flatmark T, Hough E. J. Mol. Biol. 314 279-291 (2001)
  3. The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase: implications for the catalytic mechanism. Teigen K, Frøystein NA, Martínez A. J. Mol. Biol. 294 807-823 (1999)
  4. Targeting the progression of Parkinson's disease. George JL, Mok S, Moses D, Wilkins S, Bush AI, Cherny RA, Finkelstein DI. Curr Neuropharmacol 7 9-36 (2009)
  5. Spectroscopy and kinetics of wild-type and mutant tyrosine hydroxylase: mechanistic insight into O2 activation. Chow MS, Eser BE, Wilson SA, Hodgson KO, Hedman B, Fitzpatrick PF, Solomon EI. J. Am. Chem. Soc. 131 7685-7698 (2009)
  6. Phototactic personality in fruit flies and its suppression by serotonin and white. Kain JS, Stokes C, de Bivort BL. Proc. Natl. Acad. Sci. U.S.A. 109 19834-19839 (2012)
  7. Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection. Flatmark T, Almås B, Knappskog PM, Berge SV, Svebak RM, Chehin R, Muga A, Martínez A. Eur. J. Biochem. 262 840-849 (1999)
  8. Reduction and oxidation of the active site iron in tyrosine hydroxylase: kinetics and specificity. Frantom PA, Seravalli J, Ragsdale SW, Fitzpatrick PF. Biochemistry 45 2372-2379 (2006)
  9. Identification of substrate orienting and phosphorylation sites within tryptophan hydroxylase using homology-based molecular modeling. Jiang GC, Yohrling GJ, Schmitt JD, Vrana KE. J. Mol. Biol. 302 1005-1017 (2000)
  10. The white gene of Drosophila melanogaster encodes a protein with a role in courtship behavior. Anaka M, MacDonald CD, Barkova E, Simon K, Rostom R, Godoy RA, Haigh AJ, Meinertzhagen IA, Lloyd V. J. Neurogenet. 22 243-276 (2008)
  11. Essential role of the N-terminal autoregulatory sequence in the regulation of phenylalanine hydroxylase. Jennings IG, Teh T, Kobe B. FEBS Lett. 488 196-200 (2001)
  12. Tyrosine hydroxylase activity is regulated by two distinct dopamine-binding sites. Gordon SL, Quinsey NS, Dunkley PR, Dickson PW. J. Neurochem. 106 1614-1623 (2008)
  13. Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein. Royo M, Daubner SC, Fitzpatrick PF. Proteins 58 14-21 (2005)
  14. Effects of ligands on the mobility of an active-site loop in tyrosine hydroxylase as monitored by fluorescence anisotropy. Sura GR, Lasagna M, Gawandi V, Reinhart GD, Fitzpatrick PF. Biochemistry 45 9632-9638 (2006)
  15. Self-hydroxylation of taurine/alpha-ketoglutarate dioxygenase: evidence for more than one oxygen activation mechanism. Koehntop KD, Marimanikkuppam S, Ryle MJ, Hausinger RP, Que L. J. Biol. Inorg. Chem. 11 63-72 (2006)
  16. Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Kim SW, Jung J, Oh HJ, Kim J, Lee KS, Lee DH, Park C, Kimm K, Koo SK, Jung SC. Clin. Chim. Acta 365 279-287 (2006)
  17. A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation. Daubner SC, McGinnis JT, Gardner M, Kroboth SL, Morris AR, Fitzpatrick PF. J. Mol. Biol. 359 299-307 (2006)
  18. Role of tryptophan hydroxylase phe313 in determining substrate specificity. Daubner SC, Moran GR, Fitzpatrick PF. Biochem. Biophys. Res. Commun. 292 639-641 (2002)
  19. Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite. Mexas LM, Florang VR, Doorn JA. Neurotoxicology 32 471-477 (2011)
  20. Positive charge intrinsic to Arg(37)-Arg(38) is critical for dopamine inhibition of the catalytic activity of human tyrosine hydroxylase type 1. Nakashima A, Hayashi N, Mori K, Kaneko YS, Nagatsu T, Ota A. FEBS Lett. 465 59-63 (2000)
  21. Developmental expression of tryptophan hydroxylase gene in Ciona intestinalis. Pennati R, Candiani S, Biggiogero M, Zega G, Groppelli S, Oliveri D, Parodi M, De Bernardi F, Pestarino M. Dev. Genes Evol. 217 307-313 (2007)
  22. Post-translational self-hydroxylation: a probe for oxygen activation mechanisms in non-heme iron enzymes. Farquhar ER, Koehntop KD, Emerson JP, Que L. Biochem. Biophys. Res. Commun. 338 230-239 (2005)
  23. Single turnover kinetics of tryptophan hydroxylase: evidence for a new intermediate in the reaction of the aromatic amino acid hydroxylases. Pavon JA, Eser B, Huynh MT, Fitzpatrick PF. Biochemistry 49 7563-7571 (2010)
  24. Intersubunit binding domains within tyrosine hydroxylase and tryptophan hydroxylase. Yohrling GJ, Jiang GC, Mockus SM, Vrana KE. J. Neurosci. Res. 61 313-320 (2000)
  25. The structure of formylmethanofuran: tetrahydromethanopterin formyltransferase in complex with its coenzymes. Acharya P, Warkentin E, Ermler U, Thauer RK, Shima S. J. Mol. Biol. 357 870-879 (2006)
  26. Functional analysis, using in vitro mutagenesis, of amino acids located in the phenylalanine hydroxylase active site. Jennings IG, Cotton RG, Kobe B. Arch. Biochem. Biophys. 384 238-244 (2000)
  27. Pulsed EPR study of amino acid and tetrahydropterin binding in a tyrosine hydroxylase nitric oxide complex: evidence for substrate rearrangements in the formation of the oxygen-reactive complex. Krzyaniak MD, Eser BE, Ellis HR, Fitzpatrick PF, McCracken J. Biochemistry 52 8430-8441 (2013)
  28. Mutagenesis of a specificity-determining residue in tyrosine hydroxylase establishes that the enzyme is a robust phenylalanine hydroxylase but a fragile tyrosine hydroxylase. Daubner SC, Avila A, Bailey JO, Barrera D, Bermudez JY, Giles DH, Khan CA, Shaheen N, Thompson JW, Vasquez J, Oxley SP, Fitzpatrick PF. Biochemistry 52 1446-1455 (2013)
  29. Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase. Maass A, Scholz J, Moser A. Eur. J. Biochem. 270 1065-1075 (2003)
  30. Protection from neurodegeneration in the 6-hydroxydopamine (6-OHDA) model of Parkinson's with novel 1-hydroxypyridin-2-one metal chelators. Workman DG, Tsatsanis A, Lewis FW, Boyle JP, Mousadoust M, Hettiarachchi NT, Hunter M, Peers CS, Tétard D, Duce JA. Metallomics 7 867-876 (2015)
  31. The non-canonical hydroxylase structure of YfcM reveals a metal ion-coordination motif required for EF-P hydroxylation. Kobayashi K, Katz A, Rajkovic A, Ishii R, Branson OE, Freitas MA, Ishitani R, Ibba M, Nureki O. Nucleic Acids Res. 42 12295-12305 (2014)
  32. Endogenous tetrahydroisoquinolines associated with Parkinson's disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines. Scholz J, Toska K, Luborzewski A, Maass A, Schünemann V, Haavik J, Moser A. FEBS J. 275 2109-2121 (2008)
  33. A new tyrosine hydroxylase genotype associated with early-onset severe encephalopathy. Giovanniello T, Claps D, Carducci C, Carducci C, Blau N, Vigevano F, Antonozzi I, Leuzzi V. J. Child Neurol. 27 523-525 (2012)
  34. Formation of the iron-oxo hydroxylating species in the catalytic cycle of aromatic amino acid hydroxylases. Olsson E, Martinez A, Teigen K, Jensen VR. Chemistry 17 3746-3758 (2011)
  35. XANES study of the carboxylate binding mode in two pterin hydroxylases. Mijovilovich A. Chem. Biodivers. 5 2131-2139 (2008)
  36. A conserved acidic residue in phenylalanine hydroxylase contributes to cofactor affinity and catalysis. Ronau JA, Paul LN, Fuchs JE, Liedl KR, Abu-Omar MM, Das C. Biochemistry 53 6834-6848 (2014)
  37. Landscape of protein-small ligand binding modes. Kasahara K, Kinoshita K. Protein Sci. 25 1659-1671 (2016)