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PDBsum entry 2toh

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protein ligands metals links
Hydroxylase PDB id
2toh
Jmol
Contents
Protein chain
336 a.a. *
Ligands
HBI
Metals
_FE
_CL
Waters ×172
* Residue conservation analysis
PDB id:
2toh
Name: Hydroxylase
Title: Tyrosine hydroxylase catalytic and tetramerization domains f
Structure: Tyrosine 3-monooxygenase. Chain: a. Fragment: catalytic and tetramerization domains, residues 1 synonym: tyroh. Engineered: yes. Other_details: iron and 7,8-dihydrobiopterin at the active
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Strain: bl21 (de3) plyss. Organ: adrenal gland. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: first 155 residues truncated
Biol. unit: Homo-Tetramer (from PDB file)
Resolution:
2.30Å     R-factor:   0.207     R-free:   0.276
Authors: K.E.Goodwill,C.Sabatier,R.C.Stevens
Key ref:
K.E.Goodwill et al. (1998). 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, 13437-13445. PubMed id: 9753429 DOI: 10.1021/bi981462g
Date:
26-Aug-98     Release date:   26-Aug-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04177  (TY3H_RAT) -  Tyrosine 3-monooxygenase
Seq:
Struc:
498 a.a.
336 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.14.16.2  - Tyrosine 3-monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Dopa Biosynthesis
      Reaction: L-tyrosine + tetrahydrobiopterin + O2 = L-dopa + 4a-hydroxytetrahydrobiopterin
L-tyrosine
+
tetrahydrobiopterin
Bound ligand (Het Group name = HBI)
corresponds exactly
+ O(2)
= L-dopa
+ 4a-hydroxytetrahydrobiopterin
      Cofactor: Fe cation
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     monooxygenase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi981462g Biochemistry 37:13437-13445 (1998)
PubMed id: 9753429  
 
 
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.
K.E.Goodwill, C.Sabatier, R.C.Stevens.
 
  ABSTRACT  
 
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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21351297 E.Olsson, A.Martinez, K.Teigen, and V.R.Jensen (2011).
Formation of the iron-oxo hydroxylating species in the catalytic cycle of aromatic amino acid hydroxylases.
  Chemistry, 17, 3746-3758.  
21514317 L.M.Mexas, V.R.Florang, and J.A.Doorn (2011).
Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite.
  Neurotoxicology, 32, 471-477.  
19721815 J.L.George, S.Mok, D.Moses, S.Wilkins, A.I.Bush, R.A.Cherny, and D.I.Finkelstein (2009).
Targeting the progression of Parkinson's disease.
  Curr Neuropharmacol, 7, 9.  
19489646 M.S.Chow, B.E.Eser, S.A.Wilson, K.O.Hodgson, B.Hedman, P.F.Fitzpatrick, and E.I.Solomon (2009).
Spectroscopy and kinetics of wild-type and mutant tyrosine hydroxylase: mechanistic insight into O2 activation.
  J Am Chem Soc, 131, 7685-7698.  
18972503 A.Mijovilovich (2008).
XANES study of the carboxylate binding mode in two pterin hydroxylases.
  Chem Biodivers, 5, 2131-2139.  
18355318 J.Scholz, K.Toska, A.Luborzewski, A.Maass, V.Schünemann, J.Haavik, and A.Moser (2008).
Endogenous tetrahydroisoquinolines associated with Parkinson's disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines.
  FEBS J, 275, 2109-2121.  
18513370 S.L.Gordon, N.S.Quinsey, P.R.Dunkley, and P.W.Dickson (2008).
Tyrosine hydroxylase activity is regulated by two distinct dopamine-binding sites.
  J Neurochem, 106, 1614-1623.  
17318659 R.Pennati, S.Candiani, M.Biggiogero, G.Zega, S.Groppelli, D.Oliveri, M.Parodi, F.De Bernardi, and M.Pestarino (2007).
Developmental expression of tryptophan hydroxylase gene in Ciona intestinalis.
  Dev Genes Evol, 217, 307-313.  
16878998 G.R.Sura, M.Lasagna, V.Gawandi, G.D.Reinhart, and P.F.Fitzpatrick (2006).
Effects of ligands on the mobility of an active-site loop in tyrosine hydroxylase as monitored by fluorescence anisotropy.
  Biochemistry, 45, 9632-9638.  
16320009 K.D.Koehntop, S.Marimanikkuppam, M.J.Ryle, R.P.Hausinger, and L.Que (2006).
Self-hydroxylation of taurine/alpha-ketoglutarate dioxygenase: evidence for more than one oxygen activation mechanism.
  J Biol Inorg Chem, 11, 63-72.  
16475826 P.A.Frantom, J.Seravalli, S.W.Ragsdale, and P.F.Fitzpatrick (2006).
Reduction and oxidation of the active site iron in tyrosine hydroxylase: kinetics and specificity.
  Biochemistry, 45, 2372-2379.  
16618490 S.C.Daubner, J.T.McGinnis, M.Gardner, S.L.Kroboth, A.R.Morris, and P.F.Fitzpatrick (2006).
A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation.
  J Mol Biol, 359, 299-307.  
15468323 M.Royo, S.C.Daubner, and P.F.Fitzpatrick (2005).
Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein.
  Proteins, 58, 14-21.  
15224385 H.Matter, and P.Kotsonis (2004).
Biology and chemistry of the inhibition of nitric oxide synthases by pteridine-derivatives as therapeutic agents.
  Med Res Rev, 24, 662-684.  
12631267 A.Maass, J.Scholz, and A.Moser (2003).
Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase.
  Eur J Biochem, 270, 1065-1075.  
11834745 D.M.Kuhn, M.Sadidi, X.Liu, C.Kreipke, T.Geddes, C.Borges, and J.T.Watson (2002).
Peroxynitrite-induced nitration of tyrosine hydroxylase: identification of tyrosines 423, 428, and 432 as sites of modification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and tyrosine-scanning mutagenesis.
  J Biol Chem, 277, 14336-14342.  
12009881 E.C.Wasinger, N.Mitić, B.Hedman, J.Caradonna, E.I.Solomon, and K.O.Hodgson (2002).
X-ray absorption spectroscopic investigation of the resting ferrous and cosubstrate-bound active sites of phenylalanine hydroxylase.
  Biochemistry, 41, 6211-6217.  
12039004 M.J.Ryle, and R.P.Hausinger (2002).
Non-heme iron oxygenases.
  Curr Opin Chem Biol, 6, 193-201.  
11076506 B.Almås, K.Toska, K.Teigen, V.Groehn, W.Pfleiderer, A.Martínez, T.Flatmark, and J.Haavik (2000).
A kinetic and conformational study on the interaction of tetrahydropteridines with tyrosine hydroxylase.
  Biochemistry, 39, 13676-13686.  
10900078 G.J.Yohrling, G.C.Jiang, S.M.Mockus, and K.E.Vrana (2000).
Intersubunit binding domains within tyrosine hydroxylase and tryptophan hydroxylase.
  J Neurosci Res, 61, 313-320.  
11114510 H.Erlandsen, E.E.Abola, and R.C.Stevens (2000).
Combining structural genomics and enzymology: completing the picture in metabolic pathways and enzyme active sites.
  Curr Opin Struct Biol, 10, 719-730.  
10747809 H.R.Ellis, S.C.Daubner, and P.F.Fitzpatrick (2000).
Mutation of serine 395 of tyrosine hydroxylase decouples oxygen-oxygen bond cleavage and tyrosine hydroxylation.
  Biochemistry, 39, 4174-4181.  
10986469 R.C.Stevens (2000).
Design of high-throughput methods of protein production for structural biology.
  Structure, 8, R177-R185.  
10933781 S.C.Daubner, J.Melendez, and P.F.Fitzpatrick (2000).
Reversing the substrate specificities of phenylalanine and tyrosine hydroxylase: aspartate 425 of tyrosine hydroxylase is essential for L-DOPA formation.
  Biochemistry, 39, 9652-9661.  
10691773 T.Flatmark (2000).
Catecholamine biosynthesis and physiological regulation in neuroendocrine cells.
  Acta Physiol Scand, 168, 1.  
10607676 C.J.Schofield, and Z.Zhang (1999).
Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes.
  Curr Opin Struct Biol, 9, 722-731.  
10600135 E.L.Hegg, A.K.Whiting, R.E.Saari, J.McCracken, R.P.Hausinger, and L.Que (1999).
Herbicide-degrading alpha-keto acid-dependent enzyme TfdA: metal coordination environment and mechanistic insights.
  Biochemistry, 38, 16714-16726.  
10419469 I.Rodríguez-Crespo, C.R.Nishida, G.M.Knudsen, and P.R.de Montellano (1999).
Mutation of the five conserved histidines in the endothelial nitric-oxide synthase hemoprotein domain. No evidence for a non-heme metal requirement for catalysis.
  J Biol Chem, 274, 21617-21624.  
10194366 S.C.Daubner, and P.F.Fitzpatrick (1999).
Site-directed mutants of charged residues in the active site of tyrosine hydroxylase.
  Biochemistry, 38, 4448-4454.  
10411647 T.Flatmark, B.Almås, P.M.Knappskog, S.V.Berge, R.M.Svebak, R.Chehin, A.Muga, and A.Martínez (1999).
Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection.
  Eur J Biochem, 262, 840-849.  
9875848 C.S.Raman, H.Li, P.Martásek, V.Král, B.S.Masters, and T.L.Poulos (1998).
Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center.
  Cell, 95, 939-950.
PDB codes: 1nse 2nse 3nse 4nse
9843368 H.Erlandsen, T.Flatmark, R.C.Stevens, and E.Hough (1998).
Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution.
  Biochemistry, 37, 15638-15646.
PDB codes: 3pah 4pah 5pah 6pah
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.