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Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution.

Erlandsen H, Flatmark T, Stevens RC, Hough E
Biochemistry 37 15638-46 (1998)
Related entries: 3pah, 5pah, 6pah

Cited: 34 times
EuropePMC logo PMID: 9843368

Abstract

The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes.

Reviews - 4pah mentioned but not cited (1)

  1. Tyrosine hydroxylase and regulation of dopamine synthesis. Daubner SC, Le T, Wang S. Arch Biochem Biophys 508 1-12 (2011)

Articles - 4pah mentioned but not cited (4)

  1. Improved prediction of critical residues for protein function based on network and phylogenetic analyses. Thibert B, Bredesen DE, del Rio G. BMC Bioinformatics 6 213 (2005)
  2. Efficient identification of critical residues based only on protein structure by network analysis. Cusack MP, Thibert B, Bredesen DE, Del Rio G. PLoS One 2 e421 (2007)
  3. In Silico Insight into Potential Anti-Alzheimer's Disease Mechanisms of Icariin. Cui Z, Sheng Z, Yan X, Cao Z, Tang K. Int J Mol Sci 17 E113 (2016)
  4. Rotational Spectrum and Conformational Analysis of N-Methyl-2-Aminoethanol: Insights into the Shape of Adrenergic Neurotransmitters. Calabrese C, Maris A, Evangelisti L, Piras A, Parravicini V, Melandri S. Front Chem 6 25 (2018)


Reviews citing this publication (6)

  1. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Schofield CJ, Zhang Z. Curr Opin Struct Biol 9 722-731 (1999)
  2. A Three-Ring Circus: Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the Health of Plants and Animals. Parthasarathy A, Cross PJ, Dobson RCJ, Adams LE, Savka MA, Hudson AO. Front Mol Biosci 5 29 (2018)
  3. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  4. Catecholamine biosynthesis and physiological regulation in neuroendocrine cells. Flatmark T. Acta Physiol Scand 168 1-17 (2000)
  5. The interplay of catechol ligands with nanoparticulate iron oxides. Yuen AK, Hutton GA, Masters AF, Maschmeyer T. Dalton Trans 41 2545-2559 (2012)
  6. 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)

Articles citing this publication (23)

  1. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Pey AL, Stricher F, Serrano L, Martinez A. Am J Hum Genet 81 1006-1024 (2007)
  2. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Erlandsen H, Pey AL, Gámez A, Pérez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martínez A, Stevens RC. Proc Natl Acad Sci U S A 101 16903-16908 (2004)
  3. Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation. Andersen OA, Flatmark T, Hough E. J Mol Biol 320 1095-1108 (2002)
  4. 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)
  5. 2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding. Andersen OA, Stokka AJ, Flatmark T, Hough E. J Mol Biol 333 747-757 (2003)
  6. Structural comparison of bacterial and human iron-dependent phenylalanine hydroxylases: similar fold, different stability and reaction rates. Erlandsen H, Kim JY, Patch MG, Han A, Volner A, Abu-Omar MM, Stevens RC. J Mol Biol 320 645-661 (2002)
  7. 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)
  8. 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)
  9. 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)
  10. Effects of phosphorylation by protein kinase A on binding of catecholamines to the human tyrosine hydroxylase isoforms. Sura GR, Daubner SC, Fitzpatrick PF. J Neurochem 90 970-978 (2004)
  11. Studies on the regulatory properties of the pterin cofactor and dopamine bound at the active site of human phenylalanine hydroxylase. Solstad T, Stokka AJ, Andersen OA, Flatmark T. Eur J Biochem 270 981-990 (2003)
  12. Activation of phenylalanine hydroxylase by phenylalanine does not require binding in the active site. Roberts KM, Khan CA, Hinck CS, Fitzpatrick PF. Biochemistry 53 7846-7853 (2014)
  13. Identification by hydrogen/deuterium exchange of structural changes in tyrosine hydroxylase associated with regulation. Wang S, Sura GR, Dangott LJ, Fitzpatrick PF. Biochemistry 48 4972-4979 (2009)
  14. Influence of Catecholamines (Epinephrine/Norepinephrine) on Biofilm Formation and Adhesion in Pathogenic and Probiotic Strains of Enterococcus faecalis. Cambronel M, Nilly F, Mesguida O, Boukerb AM, Racine PJ, Baccouri O, Borrel V, Martel J, Fécamp F, Knowlton R, Zimmermann K, Domann E, Rodrigues S, Feuilloley M, Connil N. Front Microbiol 11 1501 (2020)
  15. Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Bueno-Carrasco MT, Cuéllar J, Flydal MI, Santiago C, Kråkenes TA, Kleppe R, López-Blanco JR, Marcilla M, Teigen K, Alvira S, Chacón P, Martinez A, Valpuesta JM. Nat Commun 13 74 (2022)
  16. Structural and mechanistic basis of the interaction between a pharmacological chaperone and human phenylalanine hydroxylase. Torreblanca R, Lira-Navarrete E, Sancho J, Hurtado-Guerrero R. Chembiochem 13 1266-1269 (2012)
  17. Conformation and interactions of dopamine hydrochloride in solution. Callear SK, Johnston A, McLain SE, Imberti S. J Chem Phys 142 014502 (2015)
  18. Structure of full-length wild-type human phenylalanine hydroxylase by small angle X-ray scattering reveals substrate-induced conformational stability. Tomé CS, Lopes RR, Sousa PMF, Amaro MP, Leandro J, Mertens HDT, Leandro P, Vicente JB. Sci Rep 9 13615 (2019)
  19. 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)
  20. Product analog binding identifies the copper active site of particulate methane monooxygenase. Tucci FJ, Jodts RJ, Hoffman BM, Rosenzweig AC. Nat Catal 6 1194-1204 (2023)
  21. Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives. Lopes RR, Tomé CS, Russo R, Paterna R, Leandro J, Candeias NR, Gonçalves LMD, Teixeira M, Sousa PMF, Guedes RC, Vicente JB, Gois PMP, Leandro P. Biomolecules 11 462 (2021)
  22. Combined metabolomics and network pharmacology to elucidate the mechanisms of Dracorhodin Perchlorate in treating diabetic foot ulcer rats. Deng P, Liang H, Wang S, Hao R, Han J, Sun X, Pan X, Li D, Wu Y, Huang Z, Xue J, Chen Z. Front Pharmacol 13 1038656 (2022)
  23. In silico analyses of the effects of a point mutation and a pharmacological chaperone on the thermal fluctuation of phenylalanine hydroxylase. Hayakawa D, Hayakawa D, Yamaotsu N, Nakagome I, Ozawa SI, Yoshida T, Hirono S. Biophys Chem 228 47-54 (2017)


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