6pvh: Difference between revisions

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 <StructureSection load='6pvh' size='340' side='right'caption='[[6pvh]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pvh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Nrrl_746 Nrrl 746]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PVH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PVH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pvh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Penicillium_fellutanum Penicillium fellutanum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PVH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=OZ4:(7aS,12S,12aR,13aS)-3,3,12,14,14-pentamethyl-3,7,11,12,13,13a,14,15-octahydro-8H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano[3,2-a]carbazol-16-one'>OZ4</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]] 1.89&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">phqK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=70095 NRRL 746])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=OZ4:(7aS,12S,12aR,13aS)-3,3,12,14,14-pentamethyl-3,7,11,12,13,13a,14,15-octahydro-8H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano[3,2-a]carbazol-16-one'>OZ4</scene></td></tr>
-<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=6pvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pvh OCA], [http://pdbe.org/6pvh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pvh RCSB], [http://www.ebi.ac.uk/pdbsum/6pvh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pvh 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=6pvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pvh OCA], [https://pdbe.org/6pvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pvh RCSB], [https://www.ebi.ac.uk/pdbsum/6pvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pvh ProSAT]</span></td></tr>
 </table>
-<div style="background-color:#fffaf0;">
+== Function ==
-== Publication Abstract from PubMed ==
+[https://www.uniprot.org/uniprot/PHQK_PENFE PHQK_PENFE] FAD-dependent monooxygenase; part of the gene cluster that mediates the biosynthesis of paraherquamide, a fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The first steps in the biosynthesis of paraherquamide is the production of the beta-methyl-proline precursor from L-isoleucine (Probable). They require oxidation of a terminally hydroxylated L-isoleucine to the corresponding aldehyde by enzymes which have still to be identified (Probable). Spontaneous cyclization and dehydration would yield the 4-methyl pyrolline-5-carboxylic acid, which is then reduced by the pyrroline-5-carboxylate reductase phqD leading to the beta-methyl-proline precursor (Probable). The next step of paraherquamide biosynthesis involves coupling of beta-methyl-proline and L-tryptophan by the bimodular NRPS phqB, to produce a monooxopiperazine intermediate (Probable). The reductase (R) domain of phqB utilizes NADPH for hydride transfer to reduce the thioester bond of the T domain-tethered linear dipeptide to a hemithioaminal intermediate, which spontaneously cleaves the C-S bond to release the aldehyde product (PubMed:31548667). This compound undergoes spontaneous cyclization and dehydration to give a dienamine which is reverse prenylated at C-2 by the reverse prenyltransferase phqJ (Probable). The other prenyltransferase present in the cluster, phqI may be a redundant gene in the pathway (Probable). During biosynthetic assembly, the key step to produce the polycyclic core is catalyzed by the bifunctional reductase and intramolecular [4+2] Diels-Alderase, phqE, resulting in formation of the [2.2.2] diazaoctane intermediate preparaherquamide (PubMed:31548667). Following formation of preparaherquamide, an indole 2,3-epoxidation-initiated pinacol-like rearrangement is catalyzed by the phqK FAD-dependent monooxygenase (Probable). The prenyltransferase phqA, the cytochrome P450 monooxygenase phqL, and the FAD-linked oxidoreductase phqH (or the cytochrome P450 monooxygenase phqM), are proposed to be involved in the formation of the pyran ring (Probable). The FAD-dependent monooxygenase phqK is likely responsible for generation of the spiro-oxindole, and the N-methylation is likely mediated by the phqN methyltransferase leading to the isolable natural product paraherquamide F (Probable). However, the order of these biosynthetic steps has still to be determined (Probable). In late-stage paraherquamide biosynthesis, the third P450 monooxygenase, phqO, is probably responsible for the C-14 hydroxylation, transforming paraherquamide F to paraherquamide G, and paraherquamide E to the final product paraherquamide A (Probable). The expansion from the 6-membered ring pyran (in paraherquamides F and G) to the 7-membered dioxepin ring (in paraherquamides A and E) represents a poorly understood but intriguing process that probably involves the 2-oxoglutarate-dependent dioxygenase phqC (Probable). Finally, the remaining members of the paraherquamide cluster, including phqI as well as phqM (or phqH), do not have a clearly prescribed role and appear to be redundant (Probable).<ref>PMID:23213353</ref> <ref>PMID:31548667</ref> <ref>PMID:23213353</ref>
-The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a DeltaphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites, paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L is the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents.
-Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway.,Fraley AE, Caddell Haatveit K, Ye Y, Kelly SP, Newmister SA, Yu F, Williams RM, Smith JL, Houk KN, Sherman DH J Am Chem Soc. 2020 Jan 16. doi: 10.1021/jacs.9b09070. PMID:31904957<ref>PMID:31904957</ref>
+==See Also==
+*[[Monooxygenase 3D structures|Monooxygenase 3D structures]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 6pvh" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 22: / Line 18: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Nrrl 746]]
+[[Category: Penicillium fellutanum]]
-[[Category: Fraley, A E]]
+[[Category: Fraley AE]]
-[[Category: Sherman, D H]]
+[[Category: Sherman DH]]
-[[Category: Smith, J L]]
+[[Category: Smith JL]]
-[[Category: Biosynthetic protein]]
-[[Category: Flavin]]
-[[Category: Monooxygenase]]