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{{Seed}}
[[Image:2wo7.png|left|200px]]


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==Isopenicillin N synthase with substrate analogue L,L,D-ACd2Ab (unexposed)==
The line below this paragraph, containing "STRUCTURE_2wo7", creates the "Structure Box" on the page.
<StructureSection load='2wo7' size='340' side='right'caption='[[2wo7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2wo7]] 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=2WO7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WO7 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
-->
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ASV:DELTA-(L-ALPHA-AMINOADIPOYL)-L-CYSTEINYL-D-VINYLGLYCINE'>ASV</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene></td></tr>
{{STRUCTURE_2wo7| PDB=2wo7 |  SCENE= }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2wo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wo7 OCA], [https://pdbe.org/2wo7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wo7 RCSB], [https://www.ebi.ac.uk/pdbsum/2wo7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wo7 ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wo/2wo7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </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/main_output.php?pdb_ID=2wo7 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Isopenicillin N synthase (IPNS) is a non-heme iron(II) oxidase which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV). Herein we report crystallographic studies to investigate the binding of a truncated lll-substrate in the active site of IPNS. Two epimeric tripeptides have been prepared by solution phase peptide synthesis and crystallised with the enzyme. delta-l-alpha-Aminoadipoyl-l-cysteinyl-d-2-amino-3,3-dideuteriobutyrate (lld-ACd(2)Ab) has the same configuration as the natural substrate lld-ACV at each of its three stereocentres; its epimer delta-l-alpha-aminoadipoyl-l-cysteinyl-l-2-amino-3,3-dideuteriobutyrate (lll-ACd(2)Ab) has the opposite configuration at its third amino acid. lll-ACV has previously been shown to inhibit IPNS turnover of its substrate lld-ACV; the all-protiated tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-2-aminobutyrate (lld-ACAb) is a substrate for IPNS, being turned over to a mixture of penam and cepham products. Comparisons between the crystal structures of the IPNS:Fe(II):lld-ACd(2)Ab and IPNS:Fe(II):lll-ACd(2)Ab complexes offer a possible rationale for the previously observed inhibitory effects of lll-ACV on IPNS activity.


===ISOPENICILLIN N SYNTHASE WITH SUBSTRATE ANALOGUE L,L,D-ACD2AB (UNEXPOSED)===
Crystallographic studies on the binding of selectively deuterated LLD- and LLL-substrate epimers by isopenicillin N synthase.,Ge W, Clifton IJ, Stok JE, Adlington RM, Baldwin JE, Rutledge PJ Biochem Biophys Res Commun. 2010 Aug 6;398(4):659-64. Epub 2010 Jul 13. PMID:20603104<ref>PMID:20603104</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2wo7" style="background-color:#fffaf0;"></div>


<!--
==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_20603104}}, adds the Publication Abstract to the page
*[[Isopenicillin N synthase|Isopenicillin N synthase]]
(as it appears on PubMed at http://www.pubmed.gov), where 20603104 is the PubMed ID number.
== References ==
-->
<references/>
{{ABSTRACT_PUBMED_20603104}}
__TOC__
 
</StructureSection>
==About this Structure==
[[Category: Aspergillus nidulans]]
2WO7 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=2WO7 OCA].
[[Category: Large Structures]]
 
[[Category: Adlington RM]]
==Reference==
[[Category: Baldwin JE]]
<ref group="xtra">PMID:20603104</ref><references group="xtra"/>
[[Category: Clifton IJ]]
[[Category: Emericella nidulans]]
[[Category: Ge W]]
[[Category: Isopenicillin-N synthase]]
[[Category: Rutledge PJ]]
[[Category: Adlington, R M.]]
[[Category: Baldwin, J E.]]
[[Category: Clifton, I J.]]
[[Category: Ge, W.]]
[[Category: Rutledge, P J.]]
[[Category: B-lactam antibiotic]]
[[Category: Metal-binding]]
[[Category: Monocyclic intermediate]]
[[Category: Oxidoreductase]]
[[Category: Oxygenase]]
[[Category: Penicillin biosynthesis]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Aug 18 11:06:15 2010''

Latest revision as of 13:12, 20 December 2023

Isopenicillin N synthase with substrate analogue L,L,D-ACd2Ab (unexposed)Isopenicillin N synthase with substrate analogue L,L,D-ACd2Ab (unexposed)

Structural highlights

2wo7 is a 1 chain structure with sequence from Aspergillus nidulans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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) oxidase which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV). Herein we report crystallographic studies to investigate the binding of a truncated lll-substrate in the active site of IPNS. Two epimeric tripeptides have been prepared by solution phase peptide synthesis and crystallised with the enzyme. delta-l-alpha-Aminoadipoyl-l-cysteinyl-d-2-amino-3,3-dideuteriobutyrate (lld-ACd(2)Ab) has the same configuration as the natural substrate lld-ACV at each of its three stereocentres; its epimer delta-l-alpha-aminoadipoyl-l-cysteinyl-l-2-amino-3,3-dideuteriobutyrate (lll-ACd(2)Ab) has the opposite configuration at its third amino acid. lll-ACV has previously been shown to inhibit IPNS turnover of its substrate lld-ACV; the all-protiated tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-2-aminobutyrate (lld-ACAb) is a substrate for IPNS, being turned over to a mixture of penam and cepham products. Comparisons between the crystal structures of the IPNS:Fe(II):lld-ACd(2)Ab and IPNS:Fe(II):lll-ACd(2)Ab complexes offer a possible rationale for the previously observed inhibitory effects of lll-ACV on IPNS activity.

Crystallographic studies on the binding of selectively deuterated LLD- and LLL-substrate epimers by isopenicillin N synthase.,Ge W, Clifton IJ, Stok JE, Adlington RM, Baldwin JE, Rutledge PJ Biochem Biophys Res Commun. 2010 Aug 6;398(4):659-64. Epub 2010 Jul 13. PMID:20603104[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Ge W, Clifton IJ, Stok JE, Adlington RM, Baldwin JE, Rutledge PJ. Crystallographic studies on the binding of selectively deuterated LLD- and LLL-substrate epimers by isopenicillin N synthase. Biochem Biophys Res Commun. 2010 Aug 6;398(4):659-64. Epub 2010 Jul 13. PMID:20603104 doi:10.1016/j.bbrc.2010.06.129

2wo7, resolution 2.50Å

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