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| | <StructureSection load='4zum' size='340' side='right'caption='[[4zum]], [[Resolution|resolution]] 1.42Å' scene=''> | | <StructureSection load='4zum' size='340' side='right'caption='[[4zum]], [[Resolution|resolution]] 1.42Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4zum]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_49678 Atcc 49678]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZUM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4zum]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycoplana_ramosa Mycoplana ramosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZUM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZUM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FKS:7-[(3-AMINOPROPYL)AMINO]-1,1,1-TRIFLUOROHEPTANE-2,2-DIOL'>FKS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 1.42Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zun|4zun]], [[4zuo|4zuo]], [[4zup|4zup]], [[4zuq|4zuq]], [[4zur|4zur]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FKS:7-[(3-AMINOPROPYL)AMINO]-1,1,1-TRIFLUOROHEPTANE-2,2-DIOL'>FKS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">aphA, aph ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=40837 ATCC 49678])</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=4zum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zum OCA], [https://pdbe.org/4zum PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zum RCSB], [https://www.ebi.ac.uk/pdbsum/4zum PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zum ProSAT]</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=4zum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zum OCA], [http://pdbe.org/4zum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zum RCSB], [http://www.ebi.ac.uk/pdbsum/4zum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zum ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/APHA_MYCRA APHA_MYCRA]] Acts on many types of acetylpolyamines. Has high affinity towards acetylputrescine, acetylcadaverine, acetylspermidine, and acetylspermine. Acts on L-Lys-(epsilon-acetyl)-coumarin, but has very low activity towards acetylated peptides. | + | [https://www.uniprot.org/uniprot/APAH_MYCRA APAH_MYCRA] Involved in polyamine metabolism. Catalyzes the deacetylation of various acetylated polyamines such as N-acetylputrescine, N-acetylcadaverine, N(1)-acetylspermine, N(1)-acetylspermidine and N(8)-acetylspermidine (PubMed:8824626, PubMed:3207420). In vitro, is also able to deacetylate L-Lys(epsilon-acetyl)coumarin, but has very low activity towards the larger tetrapeptide N-acetyl-L-Arg-L-His-L-Lys(epsilon-acetyl)-L-Lys(epsilon-acetyl)coumarin (PubMed:21268586).<ref>PMID:21268586</ref> <ref>PMID:3207420</ref> <ref>PMID:8824626</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: Atcc 49678]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Christianson, D W]] | + | [[Category: Mycoplana ramosa]] |
| - | [[Category: Decroos, C]] | + | [[Category: Christianson DW]] |
| - | [[Category: Acetylpolyamine amidohydrolase]] | + | [[Category: Decroos C]] |
| - | [[Category: Arginase fold]]
| + | |
| - | [[Category: Enzyme-inhibitor complex]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Polyamine]]
| + | |
| Structural highlights
4zum is a 2 chain structure with sequence from Mycoplana ramosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.42Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
APAH_MYCRA Involved in polyamine metabolism. Catalyzes the deacetylation of various acetylated polyamines such as N-acetylputrescine, N-acetylcadaverine, N(1)-acetylspermine, N(1)-acetylspermidine and N(8)-acetylspermidine (PubMed:8824626, PubMed:3207420). In vitro, is also able to deacetylate L-Lys(epsilon-acetyl)coumarin, but has very low activity towards the larger tetrapeptide N-acetyl-L-Arg-L-His-L-Lys(epsilon-acetyl)-L-Lys(epsilon-acetyl)coumarin (PubMed:21268586).[1] [2] [3]
Publication Abstract from PubMed
Polyamines are essential aliphatic polycations that bind to nucleic acids and accordingly are involved in a variety of cellular processes. Polyamine function can be regulated by acetylation and deacetylation, just as histone function can be regulated by lysine acetylation and deacetylation. Acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa is a zinc-dependent polyamine deacetylase that shares approximately 20% amino acid sequence identity with human histone deacetylases. We now report the X-ray crystal structures of APAH-inhibitor complexes in a new and superior crystal form that diffracts to very high resolution (1.1-1.4 A). Inhibitors include previously synthesized analogues of N(8)-acetylspermidine bearing trifluoromethylketone, thiol, and hydroxamate zinc-binding groups [Decroos, C., Bowman, C. M., and Christianson, D. W. (2013) Bioorg. Med. Chem. 21, 4530], and newly synthesized hydroxamate analogues of shorter, monoacetylated diamines, the most potent of which is the hydroxamate analogue of N-acetylcadaverine (IC50 = 68 nM). The high-resolution crystal structures of APAH-inhibitor complexes provide key inferences about the inhibition and catalytic mechanism of zinc-dependent deacetylases. For example, the trifluoromethylketone analogue of N(8)-acetylspermidine binds as a tetrahedral gem-diol that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Surprisingly, this compound is also a potent inhibitor of human histone deacetylase 8 with an IC50 of 260 nM. Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family.
Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase.,Decroos C, Christianson DW Biochemistry. 2015 Aug 4;54(30):4692-703. doi: 10.1021/acs.biochem.5b00536. Epub , 2015 Jul 22. PMID:26200446[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lombardi PM, Angell HD, Whittington DA, Flynn EF, Rajashankar KR, Christianson DW. Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases . Biochemistry. 2011 Jan 26. PMID:21268586 doi:10.1021/bi101859k
- ↑ Fujishiro K, Ando M, Uwajima T. Crystallization and some properties of acetylpolyamine amidohydrolase from Mycoplana bullata. Biochem Biophys Res Commun. 1988 Dec 30;157(3):1169-74. PMID:3207420 doi:10.1016/s0006-291x(88)80997-5
- ↑ Sakurada K, Ohta T, Fujishiro K, Hasegawa M, Aisaka K. Acetylpolyamine amidohydrolase from Mycoplana ramosa: gene cloning and characterization of the metal-substituted enzyme. J Bacteriol. 1996 Oct;178(19):5781-6. PMID:8824626 doi:10.1128/jb.178.19.5781-5786.1996
- ↑ Decroos C, Christianson DW. Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase. Biochemistry. 2015 Aug 4;54(30):4692-703. doi: 10.1021/acs.biochem.5b00536. Epub , 2015 Jul 22. PMID:26200446 doi:http://dx.doi.org/10.1021/acs.biochem.5b00536
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