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| - | [[Image:1h19.gif|left|200px]]<br /> | |
| - | <applet load="1h19" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1h19, resolution 2.1Å" /> | |
| - | '''STRUCTURE OF [E271Q] LEUKOTRIENE A4 HYDROLASE'''<br /> | |
| | | | |
| - | ==Overview== | + | ==STRUCTURE OF [E271Q]LEUKOTRIENE A4 HYDROLASE== |
| - | Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc, metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into, leukotriene B(4), a potent chemoattractant and immune-modulating lipid, mediator. Recently, the structure of leukotriene A(4) hydrolase revealed, that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of, zinc peptidases, and Gln-136 are located at the active site. Here we, report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate, both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the, 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed, minimal conformational changes that could not explain the loss of enzyme, function. We propose that the carboxylate of Glu-271 participates in ... [[http://ispc.weizmann.ac.il/pmbin/getpm?11675384 (full description)]] | + | <StructureSection load='1h19' size='340' side='right'caption='[[1h19]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1h19]] is a 1 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=1H19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H19 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]] 2.1Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=1h19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h19 OCA], [https://pdbe.org/1h19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h19 RCSB], [https://www.ebi.ac.uk/pdbsum/1h19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h19 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/LKHA4_HUMAN LKHA4_HUMAN] Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.<ref>PMID:1897988</ref> <ref>PMID:1975494</ref> <ref>PMID:2244921</ref> <ref>PMID:12207002</ref> <ref>PMID:11917124</ref> <ref>PMID:15078870</ref> <ref>PMID:18804029</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/h1/1h19_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=1h19 ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively. |
| | | | |
| - | ==About this Structure==
| + | Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.,Rudberg PC, Tholander F, Thunnissen MM, Haeggstrom JZ J Biol Chem. 2002 Jan 11;277(2):1398-404. Epub 2001 Oct 23. PMID:11675384<ref>PMID:11675384</ref> |
| - | 1H19 is a [[http://en.wikipedia.org/wiki/Single_protein Single protein]] structure of sequence from [[http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]] with ZN, YB, IMD and ACY as [[http://en.wikipedia.org/wiki/ligands ligands]]. Active as [[http://en.wikipedia.org/wiki/Leukotriene-A(4)_hydrolase Leukotriene-A(4) hydrolase]], with EC number [[http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.6 3.3.2.6]]. Structure known Active Site: ZN1. Full crystallographic information is available from [[http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H19 OCA]].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms., Rudberg PC, Tholander F, Thunnissen MM, Haeggstrom JZ, J Biol Chem. 2002 Jan 11;277(2):1398-404. Epub 2001 Oct 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11675384 11675384]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 1h19" style="background-color:#fffaf0;"></div> |
| - | [[Category: Leukotriene-A(4) hydrolase]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Haeggstrom, J.Z.]]
| + | |
| - | [[Category: Rudberg, P.C.]]
| + | |
| - | [[Category: Tholander, F.]]
| + | |
| - | [[Category: Thunnissen, M.M.G.M.]]
| + | |
| - | [[Category: ACY]]
| + | |
| - | [[Category: IMD]]
| + | |
| - | [[Category: YB]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: alpha-beta protein]]
| + | |
| - | [[Category: hydrolase]]
| + | |
| - | [[Category: leukotriene biosynthesis]]
| + | |
| - | [[Category: metalloprotease]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Oct 30 11:07:50 2007''
| + | ==See Also== |
| | + | *[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Haeggstrom JZ]] |
| | + | [[Category: Rudberg PC]] |
| | + | [[Category: Tholander F]] |
| | + | [[Category: Thunnissen MMGM]] |
| Structural highlights
Function
LKHA4_HUMAN Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.[1] [2] [3] [4] [5] [6] [7]
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
Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively.
Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.,Rudberg PC, Tholander F, Thunnissen MM, Haeggstrom JZ J Biol Chem. 2002 Jan 11;277(2):1398-404. Epub 2001 Oct 23. PMID:11675384[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Odlander B, Claesson HE, Bergman T, Radmark O, Jornvall H, Haeggstrom JZ. Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji: indications of catalytically divergent forms of the enzyme. Arch Biochem Biophys. 1991 May 15;287(1):167-74. PMID:1897988
- ↑ Toh H, Minami M, Shimizu T. Molecular evolution and zinc ion binding motif of leukotriene A4 hydrolase. Biochem Biophys Res Commun. 1990 Aug 31;171(1):216-21. PMID:1975494
- ↑ Haeggstrom JZ, Wetterholm A, Shapiro R, Vallee BL, Samuelsson B. Leukotriene A4 hydrolase: a zinc metalloenzyme. Biochem Biophys Res Commun. 1990 Nov 15;172(3):965-70. PMID:2244921
- ↑ Thunnissen MM, Andersson B, Samuelsson B, Wong CH, Haeggstrom JZ. Crystal structures of leukotriene A4 hydrolase in complex with captopril and two competitive tight-binding inhibitors. FASEB J. 2002 Oct;16(12):1648-50. Epub 2002 Aug 7. PMID:12207002 doi:10.1096/fj.01-1017fje
- ↑ Rudberg PC, Tholander F, Thunnissen MM, Samuelsson B, Haeggstrom JZ. Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4215-20. Epub 2002 Mar 26. PMID:11917124 doi:10.1073/pnas.072090099
- ↑ Rudberg PC, Tholander F, Andberg M, Thunnissen MM, Haeggstrom JZ. Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates. J Biol Chem. 2004 Jun 25;279(26):27376-82. Epub 2004 Apr 12. PMID:15078870 doi:10.1074/jbc.M401031200
- ↑ Tholander F, Muroya A, Roques BP, Fournie-Zaluski MC, Thunnissen MM, Haeggstrom JZ. Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol. 2008 Sep 22;15(9):920-9. PMID:18804029 doi:10.1016/j.chembiol.2008.07.018
- ↑ Rudberg PC, Tholander F, Thunnissen MM, Haeggstrom JZ. Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms. J Biol Chem. 2002 Jan 11;277(2):1398-404. Epub 2001 Oct 23. PMID:11675384 doi:10.1074/jbc.M106577200
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