View source for 4zht


==Crystal structure of UDP-GlcNAc 2-epimerase==
<StructureSection load='4zht' size='340' side='right' caption='[[4zht]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4zht]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZHT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZHT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BM7:2-(ACETYLAMINO)-2-DEOXY-BETA-D-MANNOPYRANOSE'>BM7</scene>, <scene name='pdbligand=NCC:CYTIDINE-5-MONOPHOSPHATE-5-N-ACETYLNEURAMINIC+ACID'>NCC</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-N-acetylglucosamine_2-epimerase_(hydrolyzing) UDP-N-acetylglucosamine 2-epimerase (hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.183 3.2.1.183] </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=4zht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zht OCA], [http://pdbe.org/4zht PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zht RCSB], [http://www.ebi.ac.uk/pdbsum/4zht PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zht ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GLCNE_HUMAN GLCNE_HUMAN]] Defects in GNE are a cause of sialuria (SIALURIA) [MIM:[http://omim.org/entry/269921 269921]]; also known as sialuria French type. In sialuria, free sialic acid accumulates in the cytoplasm and gram quantities of neuraminic acid are secreted in the urine. The metabolic defect involves lack of feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac, resulting in constitutive overproduction of free Neu5Ac. Clinical features include variable degrees of developmental delay, coarse facial features and hepatomegaly. Sialuria inheritance is autosomal dominant.<ref>PMID:2808337</ref> <ref>PMID:10330343</ref> <ref>PMID:10356312</ref> <ref>PMID:11326336</ref>   Defects in GNE are the cause of inclusion body myopathy type 2 (IBM2) [MIM:[http://omim.org/entry/600737 600737]]. Hereditary inclusion body myopathies are a group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. IBM2 is an autosomal recessive disorder affecting mainly leg muscles, but with an unusual distribution that spares the quadriceps as also observed in Nonaka myopathy.<ref>PMID:11528398</ref> <ref>PMID:12409274</ref> <ref>PMID:12473769</ref> <ref>PMID:12473780</ref> <ref>PMID:12497639</ref> <ref>PMID:12811782</ref> <ref>PMID:15146476</ref>   Defects in GNE are the cause of Nonaka myopathy (NM) [MIM:[http://omim.org/entry/605820 605820]]; also known as distal myopathy with rimmed vacuoles (DMRV). NM is an autosomal recessive muscular disorder, allelic to inclusion body myopathy 2. It is characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood, and sparing of the quadriceps muscles. As the inclusion body myopathy, NM is histologically characterized by the presence of numerous rimmed vacuoles without inflammatory changes in muscle specimens.<ref>PMID:12325084</ref> <ref>PMID:11916006</ref> <ref>PMID:12177386</ref> <ref>PMID:12473753</ref> <ref>PMID:12913203</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/GLCNE_HUMAN GLCNE_HUMAN]] Regulates and initiates biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells.<ref>PMID:10334995</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme.

Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.,Chen SC, Huang CH, Lai SJ, Yang CS, Hsiao TH, Lin CH, Fu PK, Ko TP, Chen Y Sci Rep. 2016 Mar 16;6:23274. doi: 10.1038/srep23274. PMID:26980148<ref>PMID:26980148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4zht" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Chen, S C]]
[[Category: Chen, Y]]
[[Category: Ko, T P]]
[[Category: Yang, C S]]
[[Category: Complex]]
[[Category: Epimerase]]
[[Category: Inhibitor]]
[[Category: Isomerase]]