2y6f: Difference between revisions
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== | ==Isopenicillin N synthase with AC-D-S-methyl-3R-methylcysteine== | ||
[[2y6f]] is a 1 chain structure with sequence from [ | <StructureSection load='2y6f' size='340' side='right'caption='[[2y6f]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2y6f]] 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=2Y6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y6F FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=M9F:(2S)-2-AMINO-6-[[(2R)-1-[[(2S)-1-HYDROXY-3-METHYLSULFANYL-1-OXO-BUTAN-2-YL]AMINO]-1-OXO-3-SULFANYL-PROPAN-2-YL]AMINO]-6-OXO-HEXANOIC+ACID'>M9F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2y6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y6f OCA], [https://pdbe.org/2y6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y6f RCSB], [https://www.ebi.ac.uk/pdbsum/2y6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y6f 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Isopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non-heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution-phase incubation experiments have shown that, although IPNS can turn over analogues with a diverse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts delta-L-alpha-aminoadipoyl-L-cysteinyl-D-isoleucine (ACI) and AC-D-allo-isoleucine (ACaI) to penam products, the isosteric sulfur-containing peptides AC-D-thiaisoleucine (ACtI) and AC-D-thia-allo-isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:Fe(II) :ACtaI complex to 1.79 A resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 A from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates. | |||
Isopenicillin N Synthase Binds delta-(L-alpha-Aminoadipoyl)-L-Cysteinyl-D-Thia-allo-Isoleucine through both Sulfur Atoms.,Clifton IJ, Ge W, Adlington RM, Baldwin JE, Rutledge PJ Chembiochem. 2011 Aug 16;12(12):1881-5. doi: 10.1002/cbic.201100149. Epub, 2011 Jun 15. PMID:21678539<ref>PMID:21678539</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2y6f" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Isopenicillin N synthase|Isopenicillin N synthase]] | *[[Isopenicillin N synthase|Isopenicillin N synthase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Aspergillus nidulans]] | ||
[[Category: Clifton | [[Category: Large Structures]] | ||
[[Category: Ge | [[Category: Clifton IJ]] | ||
[[Category: Rutledge | [[Category: Ge W]] | ||
[[Category: Rutledge PJ]] | |||
Latest revision as of 11:09, 23 August 2023
Isopenicillin N synthase with AC-D-S-methyl-3R-methylcysteineIsopenicillin N synthase with AC-D-S-methyl-3R-methylcysteine
Structural highlights
FunctionIPNA_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] Publication Abstract from PubMedIsopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non-heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution-phase incubation experiments have shown that, although IPNS can turn over analogues with a diverse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts delta-L-alpha-aminoadipoyl-L-cysteinyl-D-isoleucine (ACI) and AC-D-allo-isoleucine (ACaI) to penam products, the isosteric sulfur-containing peptides AC-D-thiaisoleucine (ACtI) and AC-D-thia-allo-isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:Fe(II) :ACtaI complex to 1.79 A resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 A from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates. Isopenicillin N Synthase Binds delta-(L-alpha-Aminoadipoyl)-L-Cysteinyl-D-Thia-allo-Isoleucine through both Sulfur Atoms.,Clifton IJ, Ge W, Adlington RM, Baldwin JE, Rutledge PJ Chembiochem. 2011 Aug 16;12(12):1881-5. doi: 10.1002/cbic.201100149. Epub, 2011 Jun 15. PMID:21678539[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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