4nao
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4nao]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Claviceps_purpurea Claviceps purpurea]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NAO FirstGlance]. <br> | <table><tr><td colspan='2'>[[4nao]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Claviceps_purpurea Claviceps purpurea]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NAO FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</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]] 1.649Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</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=4nao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nao OCA], [https://pdbe.org/4nao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nao RCSB], [https://www.ebi.ac.uk/pdbsum/4nao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nao 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=4nao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nao OCA], [https://pdbe.org/4nao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nao RCSB], [https://www.ebi.ac.uk/pdbsum/4nao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nao ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/EASH_CLAP2 EASH_CLAP2] Dioxygenase; part of the gene cluster that mediates the biosynthesis of fungal ergot alkaloid (PubMed:14732265, PubMed:14700635, PubMed:15904941, PubMed:17308187, PubMed:17720822). DmaW catalyzes the first step of ergot alkaloid biosynthesis by condensing dimethylallyl diphosphate (DMAP) and tryptophan to form 4-dimethylallyl-L-tryptophan (PubMed:14732265). The second step is catalyzed by the methyltransferase easF that methylates 4-dimethylallyl-L-tryptophan in the presence of S-adenosyl-L-methionine, resulting in the formation of 4-dimethylallyl-L-abrine (By similarity). The catalase easC and the FAD-dependent oxidoreductase easE then transform 4-dimethylallyl-L-abrine to chanoclavine-I which is further oxidized by easD in the presence of NAD(+), resulting in the formation of chanoclavine-I aldehyde (PubMed:20118373, PubMed:21409592). Agroclavine dehydrogenase easG then mediates the conversion of chanoclavine-I aldehyde to agroclavine via a non-enzymatic adduct reaction: the substrate is an iminium intermediate that is formed spontaneously from chanoclavine-I aldehyde in the presence of glutathione (PubMed:20735127, PubMed:21494745). The presence of easA is not required to complete this reaction (PubMed:21494745). Further conversion of agroclavine to paspalic acid is a two-step process involving oxidation of agroclavine to elymoclavine and of elymoclavine to paspalic acid, the second step being performed by the elymoclavine oxidase cloA (PubMed:16538694, PubMed:17720822). Paspalic acid is then further converted to D-lysergic acid (PubMed:15904941). Ergopeptines are assembled from D-lysergic acid and three different amino acids by the D-lysergyl-peptide-synthetases composed each of a monomudular and a trimodular nonribosomal peptide synthetase subunit (PubMed:14700635, PubMed:15904941). LpsB and lpsC encode the monomodular subunits responsible for D-lysergic acid activation and incorporation into the ergopeptine backbone (PubMed:14700635). LpsA1 and A2 subunits encode the trimodular nonribosomal peptide synthetase assembling the tripeptide portion of ergopeptines (PubMed:14700635). LpsA1 is responsible for formation of the major ergopeptine, ergotamine, and lpsA2 for alpha-ergocryptine, the minor ergopeptine of the total alkaloid mixture elaborated by C.purpurea (PubMed:17560817, PubMed:19139103). D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases and released as N-(D-lysergyl-aminoacyl)-lactams (PubMed:24361048). Cyclolization of the D-lysergyl-tripeptides is performed by the Fe(2+)/2-ketoglutarate-dependent dioxygenase easH which introduces a hydroxyl group into N-(D-lysergyl-aminoacyl)-lactam at alpha-C of the aminoacyl residue followed by spontaneous condensation with the terminal lactam carbonyl group (PubMed:24361048).[UniProtKB:Q50EL0]<ref>PMID:14700635</ref> <ref>PMID:14732265</ref> <ref>PMID:15904941</ref> <ref>PMID:16538694</ref> <ref>PMID:17560817</ref> <ref>PMID:19139103</ref> <ref>PMID:20118373</ref> <ref>PMID:20735127</ref> <ref>PMID:21409592</ref> <ref>PMID:21494745</ref> <ref>PMID:24361048</ref> <ref>PMID:17308187</ref> <ref>PMID:17720822</ref> | [https://www.uniprot.org/uniprot/EASH_CLAP2 EASH_CLAP2] Dioxygenase; part of the gene cluster that mediates the biosynthesis of fungal ergot alkaloid (PubMed:14732265, PubMed:14700635, PubMed:15904941, PubMed:17308187, PubMed:17720822). DmaW catalyzes the first step of ergot alkaloid biosynthesis by condensing dimethylallyl diphosphate (DMAP) and tryptophan to form 4-dimethylallyl-L-tryptophan (PubMed:14732265). The second step is catalyzed by the methyltransferase easF that methylates 4-dimethylallyl-L-tryptophan in the presence of S-adenosyl-L-methionine, resulting in the formation of 4-dimethylallyl-L-abrine (By similarity). The catalase easC and the FAD-dependent oxidoreductase easE then transform 4-dimethylallyl-L-abrine to chanoclavine-I which is further oxidized by easD in the presence of NAD(+), resulting in the formation of chanoclavine-I aldehyde (PubMed:20118373, PubMed:21409592). Agroclavine dehydrogenase easG then mediates the conversion of chanoclavine-I aldehyde to agroclavine via a non-enzymatic adduct reaction: the substrate is an iminium intermediate that is formed spontaneously from chanoclavine-I aldehyde in the presence of glutathione (PubMed:20735127, PubMed:21494745). The presence of easA is not required to complete this reaction (PubMed:21494745). Further conversion of agroclavine to paspalic acid is a two-step process involving oxidation of agroclavine to elymoclavine and of elymoclavine to paspalic acid, the second step being performed by the elymoclavine oxidase cloA (PubMed:16538694, PubMed:17720822). Paspalic acid is then further converted to D-lysergic acid (PubMed:15904941). Ergopeptines are assembled from D-lysergic acid and three different amino acids by the D-lysergyl-peptide-synthetases composed each of a monomudular and a trimodular nonribosomal peptide synthetase subunit (PubMed:14700635, PubMed:15904941). LpsB and lpsC encode the monomodular subunits responsible for D-lysergic acid activation and incorporation into the ergopeptine backbone (PubMed:14700635). LpsA1 and A2 subunits encode the trimodular nonribosomal peptide synthetase assembling the tripeptide portion of ergopeptines (PubMed:14700635). LpsA1 is responsible for formation of the major ergopeptine, ergotamine, and lpsA2 for alpha-ergocryptine, the minor ergopeptine of the total alkaloid mixture elaborated by C.purpurea (PubMed:17560817, PubMed:19139103). D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases and released as N-(D-lysergyl-aminoacyl)-lactams (PubMed:24361048). Cyclolization of the D-lysergyl-tripeptides is performed by the Fe(2+)/2-ketoglutarate-dependent dioxygenase easH which introduces a hydroxyl group into N-(D-lysergyl-aminoacyl)-lactam at alpha-C of the aminoacyl residue followed by spontaneous condensation with the terminal lactam carbonyl group (PubMed:24361048).[UniProtKB:Q50EL0]<ref>PMID:14700635</ref> <ref>PMID:14732265</ref> <ref>PMID:15904941</ref> <ref>PMID:16538694</ref> <ref>PMID:17560817</ref> <ref>PMID:19139103</ref> <ref>PMID:20118373</ref> <ref>PMID:20735127</ref> <ref>PMID:21409592</ref> <ref>PMID:21494745</ref> <ref>PMID:24361048</ref> <ref>PMID:17308187</ref> <ref>PMID:17720822</ref> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | The tripeptide chains of the ergopeptines, a class of pharmacologically important D-lysergic acid alkaloid peptides, are arranged in a unique bicyclic cyclol based on an amino-terminal alpha-hydroxyamino acid and a terminal orthostructure. D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases LPS1 and LPS2 of the ergot fungus Claviceps purpurea and released as N-(D-lysergyl-aminoacyl)-lactams. We show total enzymatic synthesis of ergopeptines catalyzed by a Fe2+/2-ketoglutarate-dependent dioxygenase (EasH) in conjunction with LPS1/LPS2. Analysis of the reaction indicated that EasH introduces a hydroxyl group into N-(D-lysergyl-aminoacyl)-lactam at alpha-C of the aminoacyl residue followed by spontaneous condensation with the terminal lactam carbonyl group. Sequence analysis revealed that EasH belongs to the wide and diverse family of the phytanoyl coenzyme A hydroxylases. We provide a high-resolution crystal structure of EasH that is most similar to that of phytanoyl coenzyme A hydroxylase, PhyH, from human. | ||
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| - | Cyclolization of D-Lysergic Acid Alkaloid Peptides.,Havemann J, Vogel D, Loll B, Keller U Chem Biol. 2013 Dec 18. pii: S1074-5521(13)00417-1. doi:, 10.1016/j.chembiol.2013.11.008. PMID:24361048<ref>PMID:24361048</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4nao" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of EasH
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