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| ==Structure of SalC, a gamma-lactam-beta-lactone bicyclase for salinosporamide biosynthesis== | | ==Structure of SalC, a gamma-lactam-beta-lactone bicyclase for salinosporamide biosynthesis== |
| <StructureSection load='7s2x' size='340' side='right'caption='[[7s2x]], [[Resolution|resolution]] 2.85Å' scene=''> | | <StructureSection load='7s2x' size='340' side='right'caption='[[7s2x]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7s2x]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S2X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S2X FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S2X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S2X FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> | | </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=7s2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s2x OCA], [https://pdbe.org/7s2x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s2x RCSB], [https://www.ebi.ac.uk/pdbsum/7s2x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s2x 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=7s2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s2x OCA], [https://pdbe.org/7s2x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s2x RCSB], [https://www.ebi.ac.uk/pdbsum/7s2x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s2x ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized gamma-lactam-beta-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/beta-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-A SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.
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| Enzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead.,Bauman KD, Shende VV, Chen PY, Trivella DBB, Gulder TAM, Vellalath S, Romo D, Moore BS Nat Chem Biol. 2022 Mar 21. pii: 10.1038/s41589-022-00993-w. doi:, 10.1038/s41589-022-00993-w. PMID:35314816<ref>PMID:35314816</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7s2x" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Bauman, K D]] | | [[Category: Bauman KD]] |
| [[Category: Chen, P Y.T]] | | [[Category: Chen PY-T]] |
| [[Category: Moore, B S]] | | [[Category: Moore BS]] |
| [[Category: Trivella, D B.B]] | | [[Category: Trivella DBB]] |
| [[Category: Bicyclase]]
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| [[Category: Biosynthetic protein]]
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| [[Category: Cyclase]]
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| [[Category: Ketosynthase]]
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| [[Category: Lactam]]
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| [[Category: Lactone]]
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| [[Category: Marizomib]]
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| [[Category: Salinosporamide]]
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| [[Category: Transferase]]
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