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| - | ==ISOPENICILLIN N SYNTHASE D-(L-A-AMINOADIPOYL)-(3R)-METHYL-L-CYSTEINE D-A-HYDROXYISOVALERYL ESTER COMPLEX (ANAEROBIC)== | + | |
| - | <StructureSection load='1w3v' size='340' side='right' caption='[[1w3v]], [[Resolution|resolution]] 1.40Å' scene=''> | + | ==Isopenicillin N synthase d-(L-a-aminoadipoyl)-(3R)-methyl-L-cysteine D-a-hydroxyisovaleryl ester complex (anaerobic)== |
| | + | <StructureSection load='1w3v' size='340' side='right'caption='[[1w3v]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1w3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Emericella_nidulans Emericella nidulans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1W3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1W3V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1w3v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_nidulans Aspergillus nidulans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1W3V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1W3V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=MDZ:N~6~-METHYL-6-OXO-L-LYSINE+-+2-[(3-MERCAPTOBUTANOYL)OXY]-3-METHYLBUTANOIC+ACID'>MDZ</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]] 1.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1bk0|1bk0]], [[1blz|1blz]], [[1hb1|1hb1]], [[1hb2|1hb2]], [[1hb3|1hb3]], [[1hb4|1hb4]], [[1ips|1ips]], [[1obn|1obn]], [[1oc1|1oc1]], [[1odm|1odm]], [[1odn|1odn]], [[1qiq|1qiq]], [[1qje|1qje]], [[1qjf|1qjf]], [[1uzw|1uzw]], [[1w03|1w03]], [[1w04|1w04]], [[1w05|1w05]], [[1w06|1w06]], [[1w3x|1w3x]], [[2bjs|2bjs]], [[2bu9|2bu9]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=MDZ:N~6~-METHYL-6-OXO-L-LYSINE+-+2-[(3-MERCAPTOBUTANOYL)OXY]-3-METHYLBUTANOIC+ACID'>MDZ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PCB C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=162425 Emericella nidulans])</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=1w3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1w3v OCA], [https://pdbe.org/1w3v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1w3v RCSB], [https://www.ebi.ac.uk/pdbsum/1w3v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1w3v ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isopenicillin-N_synthase Isopenicillin-N synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.21.3.1 1.21.3.1] </span></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=1w3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1w3v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1w3v RCSB], [http://www.ebi.ac.uk/pdbsum/1w3v PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IPNS_EMENI IPNS_EMENI]] Removes, in the presence of oxygen, 4 hydrogen atoms from delta-L-(alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) to form the azetidinone and thiazolidine rings of isopenicillin. | + | [https://www.uniprot.org/uniprot/IPNA_EMENI IPNA_EMENI] Isopenicillin N synthase; part of the gene cluster that mediates the biosynthesis of penicillin, the world's most important antibiotic (PubMed:3319778, PubMed:11755401). IpnA catalyzes the cyclization of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) to form isopenicillin N (IPN) that contains the beta-lactam nucleus (PubMed:3319778, PubMed:11755401, PubMed:28703303). The penicillin biosynthesis occurs via 3 enzymatic steps, the first corresponding to the production of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) by the NRPS acvA. The tripeptide ACV is then cyclized to isopenicillin N (IPN) by the isopenicillin N synthase ipnA that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side chain is exchanged for phenylacetic acid by the isopenicillin N acyltransferase penDE to yield penicillin in the peroxisomal matrix (By similarity).[UniProtKB:P08703]<ref>PMID:11755401</ref> <ref>PMID:28703303</ref> <ref>PMID:3319778</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w3/1w3v_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w3/1w3v_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1w3v ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 1w3v" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Emericella nidulans]] | + | [[Category: Aspergillus nidulans]] |
| - | [[Category: Isopenicillin-N synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Clifton, I J]] | + | [[Category: Clifton IJ]] |
| - | [[Category: Daruzzaman, A]] | + | [[Category: Daruzzaman A]] |
| - | [[Category: Rutledge, P J]] | + | [[Category: Rutledge PJ]] |
| - | [[Category: Antibiotic biosynthesis]]
| + | |
| - | [[Category: B-lactam antibiotic]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxygenase]]
| + | |
| - | [[Category: Penicillin biosynthesis]]
| + | |
| - | [[Category: Synthase]]
| + | |
| Structural highlights
Function
IPNA_EMENI Isopenicillin N synthase; part of the gene cluster that mediates the biosynthesis of penicillin, the world's most important antibiotic (PubMed:3319778, PubMed:11755401). IpnA catalyzes the cyclization of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) to form isopenicillin N (IPN) that contains the beta-lactam nucleus (PubMed:3319778, PubMed:11755401, PubMed:28703303). The penicillin biosynthesis occurs via 3 enzymatic steps, the first corresponding to the production of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) by the NRPS acvA. The tripeptide ACV is then cyclized to isopenicillin N (IPN) by the isopenicillin N synthase ipnA that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side chain is exchanged for phenylacetic acid by the isopenicillin N acyltransferase penDE to yield penicillin in the peroxisomal matrix (By similarity).[UniProtKB:P08703][1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Isopenicillin N synthase (IPNS) is a non-heme iron(ii)-dependent oxidase that is central to penicillin biosynthesis. Herein, we report mechanistic studies of the IPNS reaction in the crystalline state, using the substrate analogue delta-(L-alpha-aminoadipoyl)-(3R)-methyl-L-cysteine D-alpha-hydroxyisovaleryl ester (AmCOV) to probe the early stages of the catalytic cycle. The X-ray crystal structure of the anaerobic IPNS:Fe(II):AmCOV complex was solved to 1.40 A resolution, and it reveals several subtle differences in the active site relative to the complex of the enzyme with its natural substrate. The crystalline IPNS:Fe(II):AmCOV complex was then exposed to oxygen gas at high pressure; this brought about reaction to give what appears to be a hydroxymethyl/ene-thiol product. A mechanism for this reaction is proposed. These results offer further insight into the delicate interplay of steric and electronic effects in the IPNS active site and the mechanistic intricacies of this remarkable enzyme.
Unexpected oxidation of a depsipeptide substrate analogue in crystalline isopenicillin N synthase.,Daruzzaman A, Clifton IJ, Adlington RM, Baldwin JE, Rutledge PJ Chembiochem. 2006 Feb;7(2):351-8. PMID:16444759[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ogle JM, Clifton IJ, Rutledge PJ, Elkins JM, Burzlaff NI, Adlington RM, Roach PL, Baldwin JE. Alternative oxidation by isopenicillin N synthase observed by X-ray diffraction. Chem Biol. 2001 Dec;8(12):1231-7. PMID:11755401
- ↑ McNeill LA, Brown TJN, Sami M, Clifton IJ, Burzlaff NI, Claridge TDW, Adlington RM, Baldwin JE, Rutledge PJ, Schofield CJ. Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non-Heme Iron Oxidases. Chemistry. 2017 Sep 18;23(52):12815-12824. doi: 10.1002/chem.201701592. Epub 2017, Aug 21. PMID:28703303 doi:http://dx.doi.org/10.1002/chem.201701592
- ↑ Ramon D, Carramolino L, Patino C, Sanchez F, Penalva MA. Cloning and characterization of the isopenicillin N synthetase gene mediating the formation of the beta-lactam ring in Aspergillus nidulans. Gene. 1987;57(2-3):171-81. doi: 10.1016/0378-1119(87)90120-x. PMID:3319778 doi:http://dx.doi.org/10.1016/0378-1119(87)90120-x
- ↑ Daruzzaman A, Clifton IJ, Adlington RM, Baldwin JE, Rutledge PJ. Unexpected oxidation of a depsipeptide substrate analogue in crystalline isopenicillin N synthase. Chembiochem. 2006 Feb;7(2):351-8. PMID:16444759 doi:10.1002/cbic.200500282
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