View source for 1fb1


==CRYSTAL STRUCTURE OF HUMAN GTP CYCLOHYDROLASE I==
<StructureSection load='1fb1' size='340' side='right'caption='[[1fb1]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1fb1]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FB1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1FB1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/GTP_cyclohydrolase_I GTP cyclohydrolase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.16 3.5.4.16] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1fb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fb1 OCA], [http://pdbe.org/1fb1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1fb1 RCSB], [http://www.ebi.ac.uk/pdbsum/1fb1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1fb1 ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:[http://omim.org/entry/233910 233910]]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.<ref>PMID:7501255</ref> <ref>PMID:9667588</ref>   Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:[http://omim.org/entry/128230 128230]]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.<ref>PMID:7501255</ref> <ref>PMID:7874165</ref> <ref>PMID:8957022</ref> <ref>PMID:8852666</ref> <ref>PMID:9120469</ref> <ref>PMID:9328244</ref> <ref>PMID:9778264</ref> <ref>PMID:10987649</ref> <ref>PMID:10582612</ref> <ref>PMID:10208576</ref> <ref>PMID:10076897</ref> <ref>PMID:10825351</ref> <ref>PMID:11113234</ref> <ref>PMID:12391354</ref> <ref>PMID:17101830</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.<ref>PMID:8068008</ref> <ref>PMID:9445252</ref> <ref>PMID:12176133</ref> <ref>PMID:16338639</ref> <ref>PMID:17057711</ref>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fb/1fb1_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1fb1 ConSurf].
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== Publication Abstract from PubMed ==
The crystal structure of recombinant human GTP cyclohydrolase I was solved by Patterson search methods by using the coordinates of the Escherichia coli enzyme as a model. The human as well as bacterial enzyme were shown to contain an essential zinc ion coordinated to a His side chain and two thiol groups in each active site of the homodecameric enzymes that had escaped detection during earlier studies of the E. coli enzyme. The zinc ion is proposed to generate a hydroxyl nucleophile for attack of imidazole ring carbon atom eight of the substrate, GTP. It may also be involved in the hydrolytic release of formate from the intermediate, 2-amino-5-formylamino-6-ribosylamino-4(3H)-pyrimidinone 5'-triphosphate, and in the consecutive Amadori rearrangement of the ribosyl moiety.

Zinc plays a key role in human and bacterial GTP cyclohydrolase I.,Auerbach G, Herrmann A, Bracher A, Bader G, Gutlich M, Fischer M, Neukamm M, Garrido-Franco M, Richardson J, Nar H, Huber R, Bacher A Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13567-72. PMID:11087827<ref>PMID:11087827</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1fb1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cyclohydrolase 3D structures|Cyclohydrolase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: GTP cyclohydrolase I]]
[[Category: Large Structures]]
[[Category: Auerbach, G]]
[[Category: Bacher, A]]
[[Category: Bader, G]]
[[Category: Bracher, A]]
[[Category: Fischer, M]]
[[Category: Garrido-Franco, M]]
[[Category: Gutlich, M]]
[[Category: Herrmann, A]]
[[Category: Huber, R]]
[[Category: Nar, H]]
[[Category: Neukamm, M]]
[[Category: Richardson, J]]
[[Category: Allosteric enzyme]]
[[Category: Hydrolase]]
[[Category: Phosphorylation]]