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New page: left|200px<br /> <applet load="1ek5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ek5, resolution 1.80Å" /> '''STRUCTURE OF HUMAN ...
 
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[[Image:1ek5.gif|left|200px]]<br />
<applet load="1ek5" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1ek5, resolution 1.80&Aring;" />
'''STRUCTURE OF HUMAN UDP-GALACTOSE 4-EPIMERASE IN COMPLEX WITH NAD+'''<br />


==Overview==
==STRUCTURE OF HUMAN UDP-GALACTOSE 4-EPIMERASE IN COMPLEX WITH NAD+==
UDP-galactose 4-epimerase catalyzes the interconversion of UDP-glucose and, UDP-galactose during normal galactose metabolism. In humans, deficiencies, in this enzyme lead to the complex disorder referred to as, epimerase-deficiency galactosemia. Here, we describe the high-resolution, X-ray crystallographic structures of human epimerase in the resting state, (i.e., with bound NAD(+)) and in a ternary complex with bound NADH and, UDP-glucose. Those amino acid side chains responsible for anchoring the, NAD(+) to the protein include Asp 33, Asn 37, Asp 66, Tyr 157, and Lys, 161. The glucosyl group of the substrate is bound to the protein via the, side-chain carboxamide groups of Asn 187 and Asn 207. Additionally, O(gamma) of Ser 132 and O(eta) of Tyr 157 lie within 2.4 and 3.1 A, respectively, of the 4'-hydroxyl group of the sugar. Comparison of the, polypeptide chains for the resting enzyme and for the protein with bound, NADH and UDP-glucose demonstrates that the major conformational changes, which occur upon substrate binding are limited primarily to the regions, defined by Glu 199 to Asp 240 and Gly 274 to Tyr 308. Additionally, this, investigation reveals for the first time that a conserved tyrosine, namely, Tyr 157, is in the proper position to interact directly with the, 4'-hydroxyl group of the sugar substrate and to thus serve as the, active-site base. A low barrier hydrogen bond between the 4'-hydroxyl, group of the sugar and O(gamma) of Ser 132 facilitates proton transfer, from the sugar 4'-hydroxyl group to O(eta) of Tyr 157.
<StructureSection load='1ek5' size='340' side='right'caption='[[1ek5]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1ek5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EK5 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ek5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ek5 OCA], [https://pdbe.org/1ek5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ek5 RCSB], [https://www.ebi.ac.uk/pdbsum/1ek5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ek5 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GALE_HUMAN GALE_HUMAN] Defects in GALE are the cause of epimerase-deficiency galactosemia (EDG) [MIM:[https://omim.org/entry/230350 230350]; also known as galactosemia type 3. Clinical features include early-onset cataracts, liver damage, deafness and mental retardation. There are two clinically distinct forms of EDG. (1) A benign, or 'peripheral' form with no detectable GALE activity in red blood cells and characterized by mild symptoms. Some patients may suffer no symptoms beyond raised levels of galactose-1-phosphate in the blood. (2) A much rarer 'generalized' form with undetectable levels of GALE activity in all tissues and resulting in severe features such as restricted growth and mental development.<ref>PMID:16302980</ref> <ref>PMID:9538513</ref> <ref>PMID:11279193</ref> <ref>PMID:9326324</ref> <ref>PMID:9973283</ref> <ref>PMID:11903335</ref> <ref>PMID:16301867</ref> <ref>PMID:15639193</ref>
== Function ==
[https://www.uniprot.org/uniprot/GALE_HUMAN GALE_HUMAN] Catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.
== 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/ek/1ek5_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=1ek5 ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known disease associated with this structure: Galactose epimerase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606953 606953]]
*[[UDP-galactose 4-epimerase|UDP-galactose 4-epimerase]]
 
== References ==
==About this Structure==
<references/>
1EK5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAD as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/UDP-glucose_4-epimerase UDP-glucose 4-epimerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.3.2 5.1.3.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EK5 OCA].
__TOC__
 
</StructureSection>
==Reference==
Crystallographic evidence for Tyr 157 functioning as the active site base in human UDP-galactose 4-epimerase., Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM, Biochemistry. 2000 May 16;39(19):5691-701. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10801319 10801319]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: UDP-glucose 4-epimerase]]
[[Category: Fridovich-Keil JL]]
[[Category: Fridovich-Keil, J.L.]]
[[Category: Holden HM]]
[[Category: Holden, H.M.]]
[[Category: Thoden JB]]
[[Category: Thoden, J.B.]]
[[Category: Wohlers TM]]
[[Category: Wohlers, T.M.]]
[[Category: NAD]]
[[Category: epimerase]]
[[Category: galactosemia]]
[[Category: short-chain dehydrogenase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:44:11 2007''

Latest revision as of 07:03, 7 February 2024

STRUCTURE OF HUMAN UDP-GALACTOSE 4-EPIMERASE IN COMPLEX WITH NAD+

1ek5, resolution 1.80Å

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