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| | <StructureSection load='4bmk' size='340' side='right'caption='[[4bmk]], [[Resolution|resolution]] 1.62Å' scene=''> | | <StructureSection load='4bmk' size='340' side='right'caption='[[4bmk]], [[Resolution|resolution]] 1.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_devorans"_zimmermann_1890 "bacillus devorans" zimmermann 1890]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BMK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Sphingomonas_paucimobilis Sphingomonas paucimobilis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BMK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MYB:DECARBOXYLATED+MYRIOCIN'>MYB</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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]] 1.62Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Serine_C-palmitoyltransferase Serine C-palmitoyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.50 2.3.1.50] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MYB:DECARBOXYLATED+MYRIOCIN'>MYB</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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=4bmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bmk OCA], [https://pdbe.org/4bmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bmk RCSB], [https://www.ebi.ac.uk/pdbsum/4bmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bmk 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=4bmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bmk OCA], [https://pdbe.org/4bmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bmk RCSB], [https://www.ebi.ac.uk/pdbsum/4bmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bmk ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/SPT_SPHPI SPT_SPHPI] Catalyzes the condensation of L-serine with palmitoyl-CoA (hexadecanoyl-CoA) to produce 3-oxosphinganine (PubMed:11279212, PubMed:17557831, PubMed:17559874, PubMed:19376777). Exhibits a broad substrate specificity concerning the chain length and the degree of unsaturation of acyl-CoA (PubMed:11279212, PubMed:19376777).<ref>PMID:11279212</ref> <ref>PMID:17557831</ref> <ref>PMID:17559874</ref> <ref>PMID:19376777</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: Bacillus devorans zimmermann 1890]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Serine C-palmitoyltransferase]] | + | [[Category: Sphingomonas paucimobilis]] |
| - | [[Category: Beattie, A E]] | + | [[Category: Beattie AE]] |
| - | [[Category: Campopiano, D J]] | + | [[Category: Campopiano DJ]] |
| - | [[Category: Clarke, D J]] | + | [[Category: Clarke DJ]] |
| - | [[Category: Dunn, T M]] | + | [[Category: Dunn TM]] |
| - | [[Category: Lowther, J]] | + | [[Category: Lowther J]] |
| - | [[Category: McMahon, S A]] | + | [[Category: McMahon SA]] |
| - | [[Category: Naismith, J H]] | + | [[Category: Naismith JH]] |
| - | [[Category: Wadsworth, J M]] | + | [[Category: Wadsworth JM]] |
| - | [[Category: Antibiotic isp-1]]
| + | |
| - | [[Category: External aldimine]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Natural product]]
| + | |
| - | [[Category: Sphingolipid]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-antibiotic complex]]
| + | |
| Structural highlights
Function
SPT_SPHPI Catalyzes the condensation of L-serine with palmitoyl-CoA (hexadecanoyl-CoA) to produce 3-oxosphinganine (PubMed:11279212, PubMed:17557831, PubMed:17559874, PubMed:19376777). Exhibits a broad substrate specificity concerning the chain length and the degree of unsaturation of acyl-CoA (PubMed:11279212, PubMed:19376777).[1] [2] [3] [4]
Publication Abstract from PubMed
Sphingolipids (SLs) are essential components of cellular membranes formed from the condensation of L-serine and a long-chain acyl thioester. This first step is catalysed by the pyridoxal 5-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) which is a promising therapeutic target. The fungal natural product myriocin is a potent inhibitor of SPT and is widely-used to block SL biosynthesis despite a lack of a detailed understanding of its molecular mechanism. By combining spectroscopy, mass spectrometry, x-ray crystallography and kinetics we have characterised the molecular details of SPT inhibition by myriocin. Myriocin initially forms an external aldimine with PLP at the active site and a structure of the resulting co-complex explains its nanomolar affinity for the enzyme. This co-complex then catalytically degrades via an unexpected 'retro-aldol like' cleavage mechanism to a C18 aldehyde which in turn acts as a suicide inhibitor of SPT by covalent modification of the essential catalytic lysine. This surprising dual mechanism of inhibition rationalises the extraordinary potency and longevity of myriocin inhibition.
The chemical basis of serine palmitoyltransferase inhibition by myriocin.,Wadsworth JM, Clarke DJ, McMahon SA, Lowther JP, Beattie AE, Langridge-Smith PR, Broughton HB, Dunn TM, Naismith JH, Campopiano DJ J Am Chem Soc. 2013 Aug 19. PMID:23957439[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ikushiro H, Hayashi H, Kagamiyama H. A water-soluble homodimeric serine palmitoyltransferase from Sphingomonas paucimobilis EY2395T strain. Purification, characterization, cloning, and overproduction. J Biol Chem. 2001 May 25;276(21):18249-56. PMID:11279212 doi:10.1074/jbc.M101550200
- ↑ Ikushiro H, Islam MM, Tojo H, Hayashi H. Molecular characterization of membrane-associated soluble serine palmitoyltransferases from Sphingobacterium multivorum and Bdellovibrio stolpii. J Bacteriol. 2007 Aug;189(15):5749-61. PMID:17557831 doi:10.1128/JB.00194-07
- ↑ Yard BA, Carter LG, Johnson KA, Overton IM, Dorward M, Liu H, McMahon SA, Oke M, Puech D, Barton GJ, Naismith JH, Campopiano DJ. The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis. J Mol Biol. 2007 Jul 27;370(5):870-86. Epub 2007 May 10. PMID:17559874 doi:10.1016/j.jmb.2007.04.086
- ↑ Raman MC, Johnson KA, Yard BA, Lowther J, Carter LG, Naismith JH, Campopiano DJ. The external aldimine form of serine palmitoyltransferase: structural, kinetic, and spectroscopic analysis of the wild-type enzyme and HSAN1 mutant mimics. J Biol Chem. 2009 Jun 19;284(25):17328-39. Epub 2009 Apr 17. PMID:19376777 doi:10.1074/jbc.M109.008680
- ↑ Wadsworth JM, Clarke DJ, McMahon SA, Lowther JP, Beattie AE, Langridge-Smith PR, Broughton HB, Dunn TM, Naismith JH, Campopiano DJ. The chemical basis of serine palmitoyltransferase inhibition by myriocin. J Am Chem Soc. 2013 Aug 19. PMID:23957439 doi:10.1021/ja4059876
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