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| | ==Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Tabun (GA)== | | ==Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Tabun (GA)== |
| - | <StructureSection load='2hrr' size='340' side='right' caption='[[2hrr]], [[Resolution|resolution]] 2.70Å' scene=''> | + | <StructureSection load='2hrr' size='340' side='right'caption='[[2hrr]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2hrr]] is a 3 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=2HRR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2HRR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2hrr]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HRR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HRR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NTJ:R-ETHYL+N,N-DIMETHYLPHOSPHONAMIDATE'>NTJ</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUC:SUCROSE'>SUC</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NTJ:R-ETHYL+N,N-DIMETHYLPHOSPHONAMIDATE'>NTJ</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FRU:FRUCTOSE'>FRU</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CES1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CES1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carboxylesterase Carboxylesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.1 3.1.1.1] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Carboxylesterase Carboxylesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.1 3.1.1.1] </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=2hrr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hrr OCA], [http://pdbe.org/2hrr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2hrr RCSB], [http://www.ebi.ac.uk/pdbsum/2hrr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2hrr ProSAT]</span></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=2hrr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hrr OCA], [https://pdbe.org/2hrr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hrr RCSB], [https://www.ebi.ac.uk/pdbsum/2hrr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hrr ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/EST1_HUMAN EST1_HUMAN]] Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate.<ref>PMID:7980644</ref> <ref>PMID:9169443</ref> | + | [[https://www.uniprot.org/uniprot/EST1_HUMAN EST1_HUMAN]] Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate.<ref>PMID:7980644</ref> <ref>PMID:9169443</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Carboxylesterase|Carboxylesterase]] | + | *[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | [[Category: Carboxylesterase]] | | [[Category: Carboxylesterase]] |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Fleming, C D]] | | [[Category: Fleming, C D]] |
| | [[Category: Redinbo, M R]] | | [[Category: Redinbo, M R]] |
| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | [[Category: Tabun]] | | [[Category: Tabun]] |
| Structural highlights
2hrr is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Gene: | CES1 (HUMAN) |
| Activity: | Carboxylesterase, with EC number 3.1.1.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[EST1_HUMAN] Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate.[1] [2]
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
The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.,Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:17407327[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brzezinski MR, Abraham TL, Stone CL, Dean RA, Bosron WF. Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine. Biochem Pharmacol. 1994 Nov 1;48(9):1747-55. PMID:7980644
- ↑ Pindel EV, Kedishvili NY, Abraham TL, Brzezinski MR, Zhang J, Dean RA, Bosron WF. Purification and cloning of a broad substrate specificity human liver carboxylesterase that catalyzes the hydrolysis of cocaine and heroin. J Biol Chem. 1997 Jun 6;272(23):14769-75. PMID:9169443
- ↑ Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR. Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun. Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:17407327 doi:10.1021/bi700246n
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