6j46

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<StructureSection load='6j46' size='340' side='right'caption='[[6j46]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
<StructureSection load='6j46' size='340' side='right'caption='[[6j46]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6j46]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfn Aspfn]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6J46 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6J46 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6j46]] 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=6J46 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6J46 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.621&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lepI, AFLA_066940 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=332952 ASPFN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
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<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=6j46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j46 OCA], [http://pdbe.org/6j46 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6j46 RCSB], [http://www.ebi.ac.uk/pdbsum/6j46 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6j46 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6j46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j46 OCA], [https://pdbe.org/6j46 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6j46 RCSB], [https://www.ebi.ac.uk/pdbsum/6j46 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6j46 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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S-adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5'-deoxy-5'-(methylthio) adenosine (MTA), S-adenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.
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Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme.,Sun Q, Hu Y, Gu Y, Huang J, He J, Luo L, Yang Y, Yin S, Dou C, Wang T, Fu X, He L, Qi S, Zhu X, Yang S, Wei X, Cheng W Signal Transduct Target Ther. 2019 May 24;4:17. doi: 10.1038/s41392-019-0052-y., eCollection 2019. PMID:31149354<ref>PMID:31149354</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6j46" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Aspfn]]
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[[Category: Aspergillus flavus NRRL3357]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Qiu, S]]
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[[Category: Qiu S]]
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[[Category: Wei, C]]
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[[Category: Wei C]]
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[[Category: Complex]]
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[[Category: Transferase]]
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Current revision

LepI-SAH complex structure

PDB ID 6j46

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