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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]]' scene=''>
<StructureSection load='7s2x' size='340' side='right'caption='[[7s2x]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<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>
<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>
</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>
</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>
<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;">
== Publication Abstract from PubMed ==
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.
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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7s2x" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bauman KD]]
[[Category: Bauman, K D]]
[[Category: Chen PY-T]]
[[Category: Chen, P Y.T]]
[[Category: Moore BS]]
[[Category: Moore, B S]]
[[Category: Trivella DBB]]
[[Category: Trivella, D B.B]]
[[Category: Bicyclase]]
[[Category: Biosynthetic protein]]
[[Category: Cyclase]]
[[Category: Ketosynthase]]
[[Category: Lactam]]
[[Category: Lactone]]
[[Category: Marizomib]]
[[Category: Salinosporamide]]
[[Category: Transferase]]
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