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| | ==Structure of the citrinin polyketide synthase CMeT domain== | | ==Structure of the citrinin polyketide synthase CMeT domain== |
| - | <StructureSection load='5mpt' size='340' side='right' caption='[[5mpt]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='5mpt' size='340' side='right'caption='[[5mpt]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mpt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_16361_[[monascus_araneosus]] Atcc 16361 [[monascus araneosus]]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MPT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MPT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mpt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Monascus_purpureus Monascus purpureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MPT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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]] 1.648Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pksCT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5098 ATCC 16361 [[Monascus araneosus]]])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mpt OCA], [http://pdbe.org/5mpt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mpt RCSB], [http://www.ebi.ac.uk/pdbsum/5mpt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mpt 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=5mpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mpt OCA], [https://pdbe.org/5mpt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mpt RCSB], [https://www.ebi.ac.uk/pdbsum/5mpt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mpt ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CITS_MONPU CITS_MONPU]] Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of the mycotoxin citrinin, a hepato-nephrotoxic compound to humans due to inhibition of respiration complex III (PubMed:16000748, PubMed:19012408, PubMed:19111642, PubMed:27913218, PubMed:28238725). The pathway begins with the synthesis of a keto-aldehyde intermediate by the citrinin PKS (pksCT) from successive condensations of 4 malonyl-CoA units, presumably with a simple acetyl-CoA starter unit (PubMed:28238725). Release of the keto-aldehyde intermediate is consistent with the presence of the C-terminal reductive release domain (PubMed:28238725). The exact catalytic role of the hydrolase mpl1 remains mysterious, although it is clear that it increases the productivity of the PKS and performs the earliest non-PKS step during citrinin biosynthesis (PubMed:27913218). Mpl2 then catalyzes the oxidation of the C-12 methyl of the ketone intermediate to an alcohol intermediate which is further oxidized by the oxidoreductase mpl7 to produce a bisaldehyde intermediate (PubMed:27913218). The fourth catalytic step is catalyzed by the mpl4 aldehyde dehydrogenase (PubMed:27913218). The final transformation is the reduction of C-3 by mpl6 to provide the chemically stable citrinin nucleus (PubMed:27913218).<ref>PMID:16000748</ref> <ref>PMID:19012408</ref> <ref>PMID:19111642</ref> <ref>PMID:27913218</ref> <ref>PMID:28238725</ref> | + | [https://www.uniprot.org/uniprot/CITS_MONPU CITS_MONPU] Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of the mycotoxin citrinin, a hepato-nephrotoxic compound to humans due to inhibition of respiration complex III (PubMed:16000748, PubMed:19012408, PubMed:19111642, PubMed:27913218, PubMed:28238725). The pathway begins with the synthesis of a keto-aldehyde intermediate by the citrinin PKS (pksCT) from successive condensations of 4 malonyl-CoA units, presumably with a simple acetyl-CoA starter unit (PubMed:28238725). Release of the keto-aldehyde intermediate is consistent with the presence of the C-terminal reductive release domain (PubMed:28238725). The exact catalytic role of the hydrolase mpl1 remains mysterious, although it is clear that it increases the productivity of the PKS and performs the earliest non-PKS step during citrinin biosynthesis (PubMed:27913218). Mpl2 then catalyzes the oxidation of the C-12 methyl of the ketone intermediate to an alcohol intermediate which is further oxidized by the oxidoreductase mpl7 to produce a bisaldehyde intermediate (PubMed:27913218). The fourth catalytic step is catalyzed by the mpl4 aldehyde dehydrogenase (PubMed:27913218). The final transformation is the reduction of C-3 by mpl6 to provide the chemically stable citrinin nucleus (PubMed:27913218).<ref>PMID:16000748</ref> <ref>PMID:19012408</ref> <ref>PMID:19111642</ref> <ref>PMID:27913218</ref> <ref>PMID:28238725</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Herbst, D A]] | + | [[Category: Large Structures]] |
| - | [[Category: Maier, T]] | + | [[Category: Monascus purpureus]] |
| - | [[Category: Storm, P A]] | + | [[Category: Herbst DA]] |
| - | [[Category: Townsend, C A]] | + | [[Category: Maier T]] |
| - | [[Category: C-methylation]] | + | [[Category: Storm PA]] |
| - | [[Category: Citrinin]] | + | [[Category: Townsend CA]] |
| - | [[Category: Domain deconstruction]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Natural product]]
| + | |
| - | [[Category: Pk]]
| + | |
| - | [[Category: Polyketide]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
CITS_MONPU Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of the mycotoxin citrinin, a hepato-nephrotoxic compound to humans due to inhibition of respiration complex III (PubMed:16000748, PubMed:19012408, PubMed:19111642, PubMed:27913218, PubMed:28238725). The pathway begins with the synthesis of a keto-aldehyde intermediate by the citrinin PKS (pksCT) from successive condensations of 4 malonyl-CoA units, presumably with a simple acetyl-CoA starter unit (PubMed:28238725). Release of the keto-aldehyde intermediate is consistent with the presence of the C-terminal reductive release domain (PubMed:28238725). The exact catalytic role of the hydrolase mpl1 remains mysterious, although it is clear that it increases the productivity of the PKS and performs the earliest non-PKS step during citrinin biosynthesis (PubMed:27913218). Mpl2 then catalyzes the oxidation of the C-12 methyl of the ketone intermediate to an alcohol intermediate which is further oxidized by the oxidoreductase mpl7 to produce a bisaldehyde intermediate (PubMed:27913218). The fourth catalytic step is catalyzed by the mpl4 aldehyde dehydrogenase (PubMed:27913218). The final transformation is the reduction of C-3 by mpl6 to provide the chemically stable citrinin nucleus (PubMed:27913218).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Fungal polyketide synthases (PKSs) are large, multidomain enzymes that biosynthesize a wide range of natural products. A hallmark of these megasynthases is the iterative use of catalytic domains to extend and modify a series of enzyme-bound intermediates. A subset of these iterative PKSs (iPKSs) contains a C-methyltransferase (CMeT) domain that adds one or more S-adenosylmethionine (SAM)-derived methyl groups to the carbon framework. Neither the basis by which only specific positions on the growing intermediate are methylated ("programming") nor the mechanism of methylation are well understood. Domain dissection and reconstitution of PksCT, the fungal non-reducing PKS (NR-PKS) responsible for the first isolable intermediate in citrinin biosynthesis, demonstrates the role of CMeT-catalyzed methylation in precursor elongation and pentaketide formation. The crystal structure of the S-adenosyl-homocysteine (SAH) coproduct-bound PksCT CMeT domain reveals a two-subdomain organization with a novel N-terminal subdomain characteristic of PKS CMeT domains and provides insights into co-factor and ligand recognition.
Functional and Structural Analysis of Programmed C-Methylation in the Biosynthesis of the Fungal Polyketide Citrinin.,Storm PA, Herbst DA, Maier T, Townsend CA Cell Chem Biol. 2017 Feb 16. pii: S2451-9456(17)30027-2. doi:, 10.1016/j.chembiol.2017.01.008. PMID:28238725[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shimizu T, Kinoshita H, Ishihara S, Sakai K, Nagai S, Nihira T. Polyketide synthase gene responsible for citrinin biosynthesis in Monascus purpureus. Appl Environ Microbiol. 2005 Jul;71(7):3453-7. PMID:16000748 doi:http://dx.doi.org/71/7/3453
- ↑ Chen YP, Tseng CP, Chien IL, Wang WY, Liaw LL, Yuan GF. Exploring the distribution of citrinin biosynthesis related genes among Monascus species. J Agric Food Chem. 2008 Dec 24;56(24):11767-72. doi: 10.1021/jf802371b. PMID:19012408 doi:http://dx.doi.org/10.1021/jf802371b
- ↑ Sakai K, Kinoshita H, Shimizu T, Nihira T. Construction of a citrinin gene cluster expression system in heterologous Aspergillus oryzae. J Biosci Bioeng. 2008 Nov;106(5):466-72. doi: 10.1263/jbb.106.466. PMID:19111642 doi:http://dx.doi.org/10.1263/jbb.106.466
- ↑ Xue Y, Kong C, Shen W, Bai C, Ren Y, Zhou X, Zhang Y, Cai M. Methylotrophic yeast Pichia pastoris as a chassis organism for polyketide synthesis via the full citrinin biosynthetic pathway. J Biotechnol. 2017 Jan 20;242:64-72. doi: 10.1016/j.jbiotec.2016.11.031. Epub, 2016 Nov 29. PMID:27913218 doi:http://dx.doi.org/10.1016/j.jbiotec.2016.11.031
- ↑ Storm PA, Herbst DA, Maier T, Townsend CA. Functional and Structural Analysis of Programmed C-Methylation in the Biosynthesis of the Fungal Polyketide Citrinin. Cell Chem Biol. 2017 Feb 16. pii: S2451-9456(17)30027-2. doi:, 10.1016/j.chembiol.2017.01.008. PMID:28238725 doi:http://dx.doi.org/10.1016/j.chembiol.2017.01.008
- ↑ Storm PA, Herbst DA, Maier T, Townsend CA. Functional and Structural Analysis of Programmed C-Methylation in the Biosynthesis of the Fungal Polyketide Citrinin. Cell Chem Biol. 2017 Feb 16. pii: S2451-9456(17)30027-2. doi:, 10.1016/j.chembiol.2017.01.008. PMID:28238725 doi:http://dx.doi.org/10.1016/j.chembiol.2017.01.008
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