Sandbox Reserved 642

This Sandbox is Reserved from 30/08/2012, through 01/02/2013 for use in the course "Proteins and Molecular Mechanisms" taught by Robert B. Rose at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 636 through Sandbox Reserved 685.

To get started: Click the edit this page tab at the top. Save the page after each step, then edit it again. Click the 3D button (when editing, above the wikitext box) to insert Jmol. show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page. Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc. More help: Help:Editing For more help, look at this link: http://proteopedia.org/w/Help:Getting_Started_in_Proteopedia Phenylalanine HydroxylasePhenylalanine Hydroxylase Phenylalanine Hydroxylase(PheOH), otherwise known as phenylalaine-4-monooxygenase, is an enzyme produced by the PAH gene found on the twelfth chromosome in the human genome, but it is also found in some bacteria. This enzyme functions as a catalyst in the conversion of the amino acids phenyalanine to tyrosine by adding a hydroxyl group (-OH) to the benzene ring of the amino acid. This is why this protein is therefore classified as a hydroxylase. In most organisms, this hydroxylation process is the first step in phenyalanine degradation. A faulty PAH gene can cause an increase in phenylalanine level in the plasma, resulting in the genetic disorder Phenylketonuria (PKU). StructureStructure spinqualitylabelsall models This is a model of the pheylalanine hydroxylase dimer as found in humans. The green ball in within each subunit represents the iron ion in the catalytic domains. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image PheOH can exist as a dimer or tetramer with identical subunits. Each subunit is organized to have a regulatory, catalytic and tetramerization domain. The native form of human PheOH has an estimated secondary structure composed 48% alpha-helices, 28% extended structures, 12% beta-turns, and 12% non-structured conformations. The more structured elements are usually concentrated in the catalytic C-terminal domain of the protein, while the more flexible and unstructured elements are grouped in the regulatory N-terminal domain. The active site of PheOH can be found in the center of the catalytic domain and is characterized by a 13 Angrstrums deep and 10 Angstrums wide hydrophobic pocket. Lining the active site are 3 glutamates, 2 histadines and 1 tyrosine residues. The center of each catalytic domain consists of an iron ion which is vital to the enzyme activity and binds to histadine residues 285 and 290, 1 oxygen atom and glutamate 330. The PheOH model protein was generated via xray crystallography. MechanismMechanism Although the exact mechanism of phenylalanine degradation is still not fully understood, the main reaction requires the addition of an hydroxyl group to the benzene ring of the phenylalanine residue. In order for this process to occur, the cofactor tetrahydrobiopterin(BH4) loses two hydrogen atoms to become dihydrobiopterin. BH4 acts as a reductant by reducing one of the diatomic oxygens while the other is added to the 6-membered ring. In order to stabilize the substrate- enzyme complex as this reaction occurs, an iron atom within the protein is necessary. It is within the active site that the hydrogen atom from phenylalanine is stripped off and replaced with a hydroxyl group. Reaction catalyzed by PheOH Implications or Possible ApplicationsImplications or Possible Applications PKU diet The absence or malfunction of the phenylalanine hydroxylase enzyme due to the mutation of the PAH gene and inheritance autosomal recessivly may result in a genetic disorder known as Phenylketonuria (PKU). Due to a diet rich in phenylalanine, this enzyme is vital in the regulation in phenylalanine plasma concentration by converting about 75% of the amino acid to tyrosine. Excessive amounts of phenylalanine has been shown to cause mental retardation in humans. Treatment for such a disease is a low phenylalanine diet, avoidance of the sweetener Aspartame, and early detection. Presently, it is regulation to screen newborns children for phenylketonuria with a simple blood or urine test. ReferencesReferences References Fusetti, F., Erlandsen,H., Flatmark, T., and Stevens, R.C., Structure of tetrameric human phenyalanine hydroxylase and its implications for phenylketonuria. (www.rcsb.org/pdb/explore/explore.do?structureID=2PAH) www.bio.davidson.edu/courses/molbio/molstudents/spring2005/castle/assign1home.html www.ncbi.nlm.nih.gov/pubmed/9490012 www.pdb.org/pdb/education_discussion/molecule_of_the_month/download/PhenylalanineHydroxylase.pdf. www.pkuworld.org/hom/docs/lierature/erlandsen_2003_p.pdf