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| | <StructureSection load='6r6u' size='340' side='right'caption='[[6r6u]], [[Resolution|resolution]] 1.71Å' scene=''> | | <StructureSection load='6r6u' size='340' side='right'caption='[[6r6u]], [[Resolution|resolution]] 1.71Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6r6u]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R6U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6r6u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R6U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.705Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACOD1, IRG1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6r6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6u OCA], [https://pdbe.org/6r6u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r6u RCSB], [https://www.ebi.ac.uk/pdbsum/6r6u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6u 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/Cis-aconitate_decarboxylase Cis-aconitate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.6 4.1.1.6] </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=6r6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6u OCA], [http://pdbe.org/6r6u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r6u RCSB], [http://www.ebi.ac.uk/pdbsum/6r6u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6u ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IRG1_HUMAN IRG1_HUMAN]] Involved in the inhibition of the inflammatory response. Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages. Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages. Plays a role in the embryo implantation.<ref>PMID:23609450</ref> <ref>PMID:23610393</ref> | + | [https://www.uniprot.org/uniprot/IRG1_HUMAN IRG1_HUMAN] Involved in the inhibition of the inflammatory response. Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages. Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages. Plays a role in the embryo implantation.<ref>PMID:23609450</ref> <ref>PMID:23610393</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: Cis-aconitate decarboxylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Blankenfeldt, W]] | + | [[Category: Blankenfeldt W]] |
| - | [[Category: Buessow, K]] | + | [[Category: Buessow K]] |
| - | [[Category: Chen, F]] | + | [[Category: Chen F]] |
| - | [[Category: Lukat, P]] | + | [[Category: Lukat P]] |
| - | [[Category: Pessler, F]] | + | [[Category: Pessler F]] |
| - | [[Category: Saile, K]] | + | [[Category: Saile K]] |
| - | [[Category: Antimicrobial]]
| + | |
| - | [[Category: Cis-aconitate]]
| + | |
| - | [[Category: Decarboxylase]]
| + | |
| - | [[Category: Immunity]]
| + | |
| - | [[Category: Inflammatory response]]
| + | |
| - | [[Category: Innate immunity]]
| + | |
| - | [[Category: Itaconate]]
| + | |
| - | [[Category: Lyase]]
| + | |
| Structural highlights
Function
IRG1_HUMAN Involved in the inhibition of the inflammatory response. Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages. Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages. Plays a role in the embryo implantation.[1] [2]
Publication Abstract from PubMed
cis-Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis-aconitate to itaconate and plays central roles in linking innate immunity with metabolism and in the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated the crystal structures of human and murine CADs and compared their enzymological properties to CAD from A. terreus Recombinant CAD is fully active in vitro without a cofactor. Murine CAD has the highest catalytic activity, whereas Aspergillus CAD is best adapted to a more acidic pH. CAD is not homologous to any known decarboxylase and appears to have evolved from prokaryotic enzymes that bind negatively charged substrates. CADs are homodimers, the active center is located in the interface between 2 distinct subdomains, and structural modeling revealed conservation in zebrafish and Aspergillus We identified 8 active-site residues critical for CAD function and rare naturally occurring human mutations in the active site that abolished CAD activity, as well as a variant (Asn152Ser) that increased CAD activity and is common (allele frequency 20%) in African ethnicity. These results open the way for 1) assessing the potential impact of human CAD variants on disease risk at the population level, 2) developing therapeutic interventions to modify CAD activity, and 3) improving CAD efficiency for biotechnological production of itaconic acid.
Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.,Chen F, Lukat P, Iqbal AA, Saile K, Kaever V, van den Heuvel J, Blankenfeldt W, Bussow K, Pessler F Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20644-20654. doi:, 10.1073/pnas.1908770116. Epub 2019 Sep 23. PMID:31548418[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Li Y, Zhang P, Wang C, Han C, Meng J, Liu X, Xu S, Li N, Wang Q, Shi X, Cao X. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J Biol Chem. 2013 Jun 7;288(23):16225-34. doi: 10.1074/jbc.M113.454538. Epub 2013, Apr 22. PMID:23609450 doi:http://dx.doi.org/10.1074/jbc.M113.454538
- ↑ Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R, Hiller K. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7820-5. doi:, 10.1073/pnas.1218599110. Epub 2013 Apr 22. PMID:23610393 doi:http://dx.doi.org/10.1073/pnas.1218599110
- ↑ Chen F, Lukat P, Iqbal AA, Saile K, Kaever V, van den Heuvel J, Blankenfeldt W, Bussow K, Pessler F. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20644-20654. doi:, 10.1073/pnas.1908770116. Epub 2019 Sep 23. PMID:31548418 doi:http://dx.doi.org/10.1073/pnas.1908770116
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