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| ==Sirtuin 5 from Danio rerio in complex with 3-hydroxy-3-methylglutaryl-CPS1 peptide== | | ==Sirtuin 5 from Danio rerio in complex with 3-hydroxy-3-methylglutaryl-CPS1 peptide== |
| <StructureSection load='5ojo' size='340' side='right' caption='[[5ojo]], [[Resolution|resolution]] 3.10Å' scene=''> | | <StructureSection load='5ojo' size='340' side='right'caption='[[5ojo]], [[Resolution|resolution]] 3.10Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[5ojo]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OJO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OJO FirstGlance]. <br> | | <table><tr><td colspan='2'>[[5ojo]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OJO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OJO FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3.1Å</td></tr> |
| <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=GZB:'>GZB</scene>, <scene name='pdbligand=HLY:'>HLY</scene>, <scene name='pdbligand=SKH:'>SKH</scene></td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GZB:2-benzamidoethanoic+acid'>GZB</scene>, <scene name='pdbligand=MAH:3-HYDROXY-3-METHYL-GLUTARIC+ACID'>MAH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ojn|5ojn]]</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=5ojo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ojo OCA], [https://pdbe.org/5ojo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ojo RCSB], [https://www.ebi.ac.uk/pdbsum/5ojo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ojo ProSAT]</span></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">sirt5, si:ch211-121a2.1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Brachidanio rerio])</td></tr>
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| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamoyl-phosphate_synthase_(ammonia) Carbamoyl-phosphate synthase (ammonia)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.16 6.3.4.16] </span></td></tr>
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| <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=5ojo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ojo OCA], [http://pdbe.org/5ojo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ojo RCSB], [http://www.ebi.ac.uk/pdbsum/5ojo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ojo ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease ==
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| [[http://www.uniprot.org/uniprot/CPSM_HUMAN CPSM_HUMAN]] Defects in CPS1 are the cause of carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:[http://omim.org/entry/237300 237300]]. CPS1D is an autosomal recessive disorder of the urea cycle causing hyperammonemia. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation.<ref>PMID:9711878</ref> <ref>PMID:12955727</ref> <ref>PMID:12655559</ref> <ref>PMID:11388595</ref> <ref>PMID:11474210</ref> <ref>PMID:15617192</ref> <ref>PMID:15164414</ref> <ref>PMID:16737834</ref> <ref>PMID:17310273</ref> <ref>PMID:20578160</ref> <ref>PMID:20520828</ref> <ref>PMID:21120950</ref> Note=Genetic variations in CPS1 influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406.<ref>PMID:20520828</ref>
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| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/SIR5_DANRE SIR5_DANRE]] NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo (By similarity). [[http://www.uniprot.org/uniprot/CPSM_HUMAN CPSM_HUMAN]] Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell. | | [https://www.uniprot.org/uniprot/SIR5_DANRE SIR5_DANRE] NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo (By similarity). |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators.
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| Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features.,Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C Nat Commun. 2017 Nov 15;8(1):1513. doi: 10.1038/s41467-017-01701-2. PMID:29138502<ref>PMID:29138502</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 5ojo" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Histone deacetylase|Histone deacetylase]] | | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Brachidanio rerio]] | | [[Category: Danio rerio]] |
| [[Category: Pannek, M]] | | [[Category: Large Structures]] |
| [[Category: Steegborn, C]] | | [[Category: Synthetic construct]] |
| [[Category: Deacylase]] | | [[Category: Pannek M]] |
| [[Category: Mitochondria]] | | [[Category: Steegborn C]] |
| [[Category: Signaling protein]]
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| [[Category: Sirt5]]
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| [[Category: Sirtuin]]
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