Sandbox Reserved 772: Difference between revisions

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OCA, Jah Ia Yang

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-<Structure load='1K75' size='500' frame='true' align='right' caption='INSERT CAPTION HERE' scene='Insert optional scene name here' />
+<Structure load='1k75' size='500' frame='true' align='right' caption='Crystal structure of L-histidinol dehydrogenase with a functional homodimer in the asymmetric unit.' /><ref name="pymol">The JyMOL Molecular Graphics System, Version 1.0, Schrödinger, LLC.</ref>
-[[Image:PDB_1k75_EBI.jpg |thumb |this is a caption ]]
+[[Image:PDB_1k75_EBI.jpg |left|250px]]
 ==Histidinol Dehydrogenase==
-Histidinol dehydrogenase (HDH) is coded by the structural gene hisD.  Histidinol dehydrogenase catalyzes the last step in the histidine biosynthetic pathway.  This pathway was found in bacteria, archaebacteria, fungi, and plants.  The pathway involves the conversion of L-histidinol to L-histidine with a L-histidinaldehyde intermediate <ref name="pnas">http://www.pnas.org.prox.lib.ncsu.edu/content/99/4/1859.full.pdf</ref>
+Histidinol dehydrogenase (HDH) is an enzyme that catalyzes the last step in the histidine biosynthetic pathway, which converts L-histidinol to L-histidine with a L-histidinaldehyde intermediate.  This primordial pathway was found in bacteria, archaebacteria, fungi, and plants.  HDH has been one of the most studied enzyme biochemically and genetically throughout time.<ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199<http://www.pnas.org.prox.lib.ncsu.edu/content/99/4/1859.full.pdf></ref>
+HDH is encoded by the structural gene ''hisD'' in Brucellosis, commonly known as Maltafeve.  Brucellosis is a bacterial disease transmitted by having contact with infected animals.  HDH being encoded by ''hisD'' is essential for intramacrophagic replication because it provides a novel target for the development of anti-Brucella agent.<ref name="article5">J. Pascale, M. Abdo, R. Boigegrain, J. Montero, J. Winum, S. Kohler. "Targeting of the Brucella Suis Virulence Factor Histidinol Dehydrogenase by Histidinol Analogues Results in Inhibition of Intramacrophagic Multiplication of the Pathogen." American Society for Microbiology (2007): N. pag. Web. 27 Nov. 2013. <http://aac.asm.org/content/51/10/3752.short>.</ref>  Because HDH is absent from mammals, it has become an attractive target for inhibition as part of the herbicide development.<ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199</ref>
 __TOC__
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 '''Gene Name''': hisD <ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>
-'''Organism''': Escherichia coli (strain K12) <ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>
+'''Organism''': ''Escherichia coli'' (strain K12) <ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>
-'''Classification''': Oxidoreductase
+'''Classification''': Oxidoreductase <ref name="cite2">http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K75</ref>
-'''Length''': 434 Amino Acids <ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>
+'''Length''': 434 Residues <ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>
-'''Chains''': A, B <ref name="cite2">http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K75</ref>
+'''Molecular Weight''': 46107.65 Da <ref name="cite3">http://www.topsan.org/Proteins/BSGI/1k75</ref>
-'''Molecular Weight''':
+'''Isoelectric Point''': 5.06 <ref name="cite3">http://www.topsan.org/Proteins/BSGI/1k75</ref>
-'''Isoelectric Point''':
+'''Chains''': <scene name='56/564048/Chain_a/2'>A</scene>, <scene name='56/564048/Chain_b/2'>B</scene> <ref name="cite2">http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K75</ref>
-'''Km''':
+'''Ligands''': glycerol ([http://oca.weizmann.ac.il/oca-bin/send-het?GOL GOL]), selenomethionine ([http://oca.weizmann.ac.il/oca-bin/send-het?MSE MSE]), sulfate ion ([http://oca.weizmann.ac.il/oca-bin/send-het?SO4 SO4])<ref name="cite2">http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K75</ref>
-'''Vmax''':
 ==Structure==
+The crystal structure of histidinol dehydrogenase can be determined by x-ray crystallography.  The overall structure is 48% helical (20 helices; 211 residues) and 16% beta sheet (15 strands; 73 residues).<ref name="structure">http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=1K75&bionumber=1</ref>
+HDH functions as a homodimer, but it consists of two monomers.  The presence of Zn2+ cation is required per monomer.  Each HDH monomer is made of four domains, two larger domains and two smaller domains.  The two larger domains make up the globule and the two smaller domains make up the extending tail.  The intertwined dimer is thought to result from domain swapping.  The two domains presents a similar incomplete Rossmann fold, which suggests an ancient event of gene duplication.  Residues from both monomers form the active site. The active site (residue His-327) participates in acid-base catalysis <ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199</ref>
-HisD is a monomer, but it functions as a homodimer.  The presence of Zn2+ cation is required per monomer.  Each hisD monomer is made of four domains,two larger domains (globule) and two smaller domains (extending tail), whereas the intertwined dimer possibly results from domain swapping. Two domains display a very similar incomplete Rossmann fold that suggests an ancient event of gene duplication. Residues from both monomers form the active site. The active site, residue His-327, participates in acid-base catalysis <ref name="pnas">http://www.pnas.org.prox.lib.ncsu.edu/content/99/4/1859.full.pdf</ref>
+'''Related Structures''': [http://proteopedia.org/wiki/index.php/1kae 1KAE] and [http://proteopedia.org/wiki/index.php/1kar 1KAR]
-For the overall structure, it is 48% helical (20 helices; 211 residues) and 16% beta sheet (15 strands; 73 residues). <ref name="structure">http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=1K75&bionumber=1</ref>
+[[Image:Monomer.gif |300px]]<ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199</ref>
-'''Related Structures''': [http://proteopedia.org/wiki/index.php/1kae 1KAE] and [http://proteopedia.org/wiki/index.php/1kar 1KAR]
+'''Figure 1.''' ''(A) Stereo view of the monomer. Domains: 1, blue; 2, green; 3, orange; 4, magenta. L-histidinol, NAD, and the Zn2� are shown as ball-and-sticks. ( B) Domain 1. Rossmann fold shown in blue, V-shaped pairs of helices (residues 25 –103) connected by a linker that forms the sixth strand are in cyan. (C) Domain 2. Rossmann fold (green) in similar orientation as B. Strand-helix hairpin completes the �-sheet (residues 1–24, magenta). (D) Topology diagram. Secondary structure elements are numbered consecutively. The chain meanders between domains in the order 2 –1-3–1-2–1-3– 4. (E) HisD dimer with one molecule colored as in A and the other shown in pale colors. Zn2� atoms and NAD bound to each monomer (red) define the position of the active site.<ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199<http://www.pnas.org.prox.lib.ncsu.edu/content/99/4/1859.full.pdf></ref> ''
+'''Sequence of HDH''' <ref name="structure">http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=1K75&bionumber=1</ref>
+[[Image:403px-Histidine decarboxylase seq.png |300px]]
+'''Figure. 2''' ''This is the full sequence of histidinol dehydrogenase.''
 ==Enzymatic Mechanism==
 [[Image:pathways.jpg]]
-This bifunctional enzyme converts L-histidinol to L-histidine through a L-histidinaldehyde intermediate. <ref name="pnas">http://www.pnas.org.prox.lib.ncsu.edu/content/99/4/1859.full.pdf</ref>
+'''Figure 3.''' ''This bifunctional enzyme converts L-histidinol to L-histidine through a L-histidinaldehyde intermediate. His-327 and Glu-326 are the two main active sites of HDH.<ref name="info">http://www.uniprot.org/uniprot/P06988#section_terms</ref>''
+The reaction above is as follows:
+-1 proton and 1 hydride are abstracted from L-histidinol by His-327 (B1).  NAD+ accepts hydride.
+-L-histdinol becomes L-histidinaldehyde (sp2)
+-Reduced NADH cofactor leaves and then is replaced by another NAD+
+-Water is activated by Glu-326  (B2) and makes a nucleophilic attack on the reactive carbon.
+-Concurrently, His-327 (B3) donates its proton to the aldehyde oxygen
+-Repeat step 1 and then it leads to the formation of L-histidine <ref name="pnas">PNAS 2002 99 (4) 1859-1864; published ahead of print February 12, 2002, doi:10.1073/pnas.022476199</ref>
+==Implications or Possible Applications==
+Brucellosis, commonly known as Maltafever, is the most widespread bacterial zoonosis worldwide.  It is a bacterial disease of human beings transmitted by contact with infected animals or infected meat or milk products.  It causes fever and headaches. Its causative agent, Brucella spp., is a facultative intracellular pathogen developed inside the host’s macrophages.
+The absence of a vaccine for humans and the appearing resistance of Brucella spp. to anti-biotic chemotherapy points to the necessity to develop new therapeutic strategies to eradicate this reemerging pathogen.  The virulome analysis of Brucella suis shows that genes involved in the biosynthesis of amino acids are essential for the virulence of the bacteria.
+Inhibition of its enzymatic activity with specific inhibitors will prevent intramacrophagic multiplication of Brucella.  Histidinol dehydrogenase is an amino acid biosynthetic enzyme, which can provide a novel target for the development of anti-Brucella agents.  Histidinol dehydrogenase has no counterpart in mammalians; therefore, it constitutes a therapeutic target for the development of an anti-infectious treatment against intracellular pathogens.<ref name="article2">Turtaut, Francois, Safia Ouahrani-Bettache, Jean Montero, Stephan Kohler, and Jean-Yves Winum. "Synthesis and Biological Evaluation of a New Class of Anti-brucella Compounds Targeting Histidinol Dehydrogenase: α-O-arylketones and α-S-arylketones Derived from Histidine." Med. Chem. Commun. 2(2011): 995-1000. Web. 27 Nov. 2013. <http://pubs.rsc.org.prox.lib.ncsu.edu/en/Content/ArticleLanding/2011/MD/c1md00146a#!divCitation>.</ref>
 ==References==
 <references />