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| | ==Small-molecule inhibition of ppGalNAc-Ts selectively reduces mucin-type O-glycosylation== | | ==Small-molecule inhibition of ppGalNAc-Ts selectively reduces mucin-type O-glycosylation== |
| - | <StructureSection load='5ndf' size='340' side='right' caption='[[5ndf]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='5ndf' size='340' side='right'caption='[[5ndf]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ndf]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NDF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NDF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ndf]] is a 6 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=5NDF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NDF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LU2:2-(3,4-DIHYDROXYPHENYL)-5,7-DIHYDROXY-4H-CHROMEN-4-ONE'>LU2</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Polypeptide_N-acetylgalactosaminyltransferase Polypeptide N-acetylgalactosaminyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.41 2.4.1.41] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LU2:2-(3,4-DIHYDROXYPHENYL)-5,7-DIHYDROXY-4H-CHROMEN-4-ONE'>LU2</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></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=5ndf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ndf OCA], [http://pdbe.org/5ndf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ndf RCSB], [http://www.ebi.ac.uk/pdbsum/5ndf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ndf ProSAT]</span></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=5ndf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ndf OCA], [https://pdbe.org/5ndf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ndf RCSB], [https://www.ebi.ac.uk/pdbsum/5ndf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ndf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GALT2_HUMAN GALT2_HUMAN]] Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a broad spectrum of substrates for peptides such as EA2, Muc5AC, Muc1a, Muc1b. Probably involved in O-linked glycosylation of the immunoglobulin A1 (IgA1) hinge region.<ref>PMID:9295285</ref> <ref>PMID:12438318</ref> | + | [https://www.uniprot.org/uniprot/GALT2_HUMAN GALT2_HUMAN] Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a broad spectrum of substrates for peptides such as EA2, Muc5AC, Muc1a, Muc1b. Probably involved in O-linked glycosylation of the immunoglobulin A1 (IgA1) hinge region.<ref>PMID:9295285</ref> <ref>PMID:12438318</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Polypeptide N-acetylgalactosaminyltransferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hurtado-Guerrero, R]] | + | [[Category: Large Structures]] |
| - | [[Category: Rivas, M De las]] | + | [[Category: De las Rivas M]] |
| - | [[Category: Galnac-t2 inhibition flavonoids mucin-type o-glycosylation alzheimer disease]] | + | [[Category: Hurtado-Guerrero R]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
GALT2_HUMAN Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a broad spectrum of substrates for peptides such as EA2, Muc5AC, Muc1a, Muc1b. Probably involved in O-linked glycosylation of the immunoglobulin A1 (IgA1) hinge region.[1] [2]
Publication Abstract from PubMed
Mucin-type O-glycosylation is the most abundant type of O-glycosylation. It is initiated by the members of polypeptide N-acetyl-alpha-galactosaminyltransferase (ppGalNAc-T) family and closely associated with both physiological and pathological conditions such as coronary artery disease or Alzheimer' s disease. The lack of direct and selective inhibitors of ppGalNAc-Ts has largely impeded research progress in understanding the molecular events in mucin-type O-glycosylation. Here, we report that a small molecule, the plant flavonoid luteolin, selectively inhibits ppGalNAc-Ts in vitro and in cells. We found that luteolin inhibits ppGalNAc-T2 through a peptide/protein-competitive manner but not promiscuously, e.g. via aggregation-based activity. X-ray structural analysis revealed that luteolin binds to the PxP motif-binding site found in most protein substrates, which was further validated by comparing the interactions between luteolin with wildtype enzyme and mutants using 1H NMR-based binding experiments. Functional studies disclosed that luteolin at least partially reduced production of beta-amyloid (Abeta) protein by selectively inhibiting the activity of ppGalNAc-T isoforms. In conclusion, our study provides key structural and functional details on luteolin inhibiting ppGalNAc-T activity, opening up the way for further optimization of more potent and specific ppGalNAc-T inhibitors. Moreover, our findings may inform future investigations into site-specific O-GalNAc glycosylation and into the molecular mechanism of luteolin-mediated ppGalNAc-T inhibition.
The small molecule luteolin inhibits N-acetyl-alpha-galactosaminyltransferases and reduces mucin-type O-glycosylation of amyloid precursor protein.,Liu F, Xu K, Xu Z, Rivas ML, Li X, Lu J, Delso I, Merino P, Hurtado-Guerrero R, Zhang Y J Biol Chem. 2017 Oct 23. pii: jbc.M117.814202. doi: 10.1074/jbc.M117.814202. PMID:29061849[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wandall HH, Hassan H, Mirgorodskaya E, Kristensen AK, Roepstorff P, Bennett EP, Nielsen PA, Hollingsworth MA, Burchell J, Taylor-Papadimitriou J, Clausen H. Substrate specificities of three members of the human UDP-N-acetyl-alpha-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase family, GalNAc-T1, -T2, and -T3. J Biol Chem. 1997 Sep 19;272(38):23503-14. PMID:9295285
- ↑ Iwasaki H, Zhang Y, Tachibana K, Gotoh M, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Kubota T, Narimatsu H. Initiation of O-glycan synthesis in IgA1 hinge region is determined by a single enzyme, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2. J Biol Chem. 2003 Feb 21;278(8):5613-21. Epub 2002 Nov 15. PMID:12438318 doi:http://dx.doi.org/10.1074/jbc.M211097200
- ↑ Liu F, Xu K, Xu Z, Rivas ML, Li X, Lu J, Delso I, Merino P, Hurtado-Guerrero R, Zhang Y. The small molecule luteolin inhibits N-acetyl-alpha-galactosaminyltransferases and reduces mucin-type O-glycosylation of amyloid precursor protein. J Biol Chem. 2017 Oct 23. pii: jbc.M117.814202. doi: 10.1074/jbc.M117.814202. PMID:29061849 doi:http://dx.doi.org/10.1074/jbc.M117.814202
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