View source for 2yhy


==Structure of N-Acetylmannosamine kinase in complex with N- acetylmannosamine and ADP==
<StructureSection load='2yhy' size='340' side='right'caption='[[2yhy]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2yhy]] 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=2YHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YHY 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]] 1.82&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=BM3:2-(ACETYLAMINO)-2-DEOXY-ALPHA-D-MANNOPYRANOSE'>BM3</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2yhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yhy OCA], [https://pdbe.org/2yhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yhy RCSB], [https://www.ebi.ac.uk/pdbsum/2yhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yhy ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GLCNE_HUMAN GLCNE_HUMAN] Defects in GNE are a cause of sialuria (SIALURIA) [MIM:[https://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:[https://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:[https://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 ==
[https://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 ==
Sialic acids are essential components of membrane glycoconjugates. They are responsible for the interaction, structure, and functionality of all deuterostome cells and have major functions in cellular processes in health and diseases. The key enzyme of the biosynthesis of sialic acid is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase that transforms UDP-N-acetylglucosamine to N-acetylmannosamine (ManNAc) followed by its phosphorylation to ManNAc 6-phosphate and has a direct impact on the sialylation of cell surface components. Here, we present the crystal structures of the human N-acetylmannosamine kinase (MNK) domain of UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase in complexes with ManNAc at 1.64 A resolution, MNK.ManNAc.ADP (1.82 A) and MNK.ManNAc 6-phosphate.ADP (2.10 A). Our findings offer detailed insights in the active center of MNK and serve as a structural basis to design inhibitors. We synthesized a novel inhibitor, 6-O-acetyl-ManNAc, which is more potent than those previously tested. Specific inhibitors of sialic acid biosynthesis may serve to further study biological functions of sialic acid.

Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition.,Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S J Biol Chem. 2012 Apr 20;287(17):13656-65. Epub 2012 Feb 16. PMID:22343627<ref>PMID:22343627</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2yhy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fan H]]
[[Category: Hinderlich S]]
[[Category: Martinez J]]
[[Category: Moniot S]]
[[Category: Nguyen LD]]
[[Category: Reutter W]]
[[Category: Saenger W]]
[[Category: Tauberger E]]