View source for 6ix7


==The structure of LepI C52A in complex with SAH and substrate analogue==
<StructureSection load='6ix7' size='340' side='right'caption='[[6ix7]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ix7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_flavus_NRRL3357 Aspergillus flavus NRRL3357]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IX7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IX7 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]] 1.835&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B0L:4-hydroxy-3-[(2S,6E,8E)-2-methyldeca-6,8-dienoyl]-5-phenylpyridin-2(1H)-one'>B0L</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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=6ix7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ix7 OCA], [https://pdbe.org/6ix7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ix7 RCSB], [https://www.ebi.ac.uk/pdbsum/6ix7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ix7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LEPI_ASPFN LEPI_ASPFN] O-methyltransferase; part of the gene cluster 23 that mediates the biosynthesis of a family of 2-pyridones known as leporins (PubMed:20447271, PubMed:26051490). The hybrid PKS-NRPS synthetase lepA and the enoyl reductase lepG are responsible for fusion of phenylalanine with a hexaketide and subsequent release of the stable tetramic acid precursor, pre-leporin C (PubMed:26051490). Because lepA lacks a designated enoylreductase (ER) domain, the required activity is provided the enoyl reductase lepG (PubMed:26051490). It is possible that the dehydrogenase lepF also participates in production of pre-leporin C (PubMed:26051490). Cytochrome P450 monooxygenase lepH is then required for the ring expansion step to yield leporin C (PubMed:26051490). Leporin C is then presumably further oxidized by the N-hydroxylase lepD to form leporin B (PubMed:26051490). LepI may possess a function in biosynthesis upstream of lepA (PubMed:26051490). Leporin B is further oxidized in the presence of ferric ion to give the leporin B trimer-iron chelate, but whether or not this reaction is catalyzed by an enzyme in the pathway or by ferric ion is not determined yet (PubMed:26051490).<ref>PMID:26051490</ref> <ref>PMID:20447271</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
LepI is an S-adenosylmethionine (SAM)-dependent pericyclase that catalyses the formation of the 2-pyridone natural product leporin C. Biochemical characterization has shown that LepI can catalyse stereoselective dehydration to yield a reactive (E)-quinone methide that can undergo bifurcating intramolecular Diels-Alder (IMDA) and hetero-Diels-Alder (HDA) cyclizations from an ambimodal transition state, as well as a [3,3]-retro-Claisen rearrangement to recycle the IMDA product into leporin C. Here, we solve the X-ray crystal structures of SAM-bound LepI and in complex with a substrate analogue, the product leporin C, and a retro-Claisen reaction transition-state analogue to understand the structural basis for the multitude of reactions. Structural and mutational analysis reveals how nature evolves a classic methyltransferase active site into one that can serve as a dehydratase and a multifunctional pericyclase. Catalysis of both sets of reactions employs H133 and R295, two active-site residues that are not found in canonical methyltransferases. An alternative role of SAM, which is not found to be in direct contact with the substrate, is also proposed.

Structural basis for stereoselective dehydration and hydrogen-bonding catalysis by the SAM-dependent pericyclase LepI.,Cai Y, Hai Y, Ohashi M, Jamieson CS, Garcia-Borras M, Houk KN, Zhou J, Tang Y Nat Chem. 2019 Jul 22. pii: 10.1038/s41557-019-0294-x. doi:, 10.1038/s41557-019-0294-x. PMID:31332284<ref>PMID:31332284</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ix7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Aspergillus flavus NRRL3357]]
[[Category: Large Structures]]
[[Category: Cai Y]]
[[Category: Hai Y]]
[[Category: Ohashi M]]
[[Category: Tang Y]]
[[Category: Zhou J]]