3zs1: Difference between revisions
No edit summary |
No edit summary |
||
| (7 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Human Myeloperoxidase inactivated by TX5== | |||
<StructureSection load='3zs1' size='340' side='right'caption='[[3zs1]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3zs1]] is a 4 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=3ZS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZS1 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]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PVW:3-(2-METHOXYETHYL)-2-THIOXO-1,2,3,7-TETRAHYDRO-6H-PURIN-6-ONE'>PVW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=3zs1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs1 OCA], [https://pdbe.org/3zs1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zs1 RCSB], [https://www.ebi.ac.uk/pdbsum/3zs1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs1 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN] Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:[https://omim.org/entry/254600 254600]. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.<ref>PMID:8142659</ref> <ref>PMID:7904599</ref> <ref>PMID:8621627</ref> <ref>PMID:9637725</ref> <ref>PMID:9354683</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN] Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation. | |||
2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.,Tiden AK, Sjogren T, Svensson M, Bernlind A, Senthilmohan R, Auchere F, Norman H, Markgren PO, Gustavsson S, Schmidt S, Lundquist S, Forbes LV, Magon NJ, Paton LN, Jameson GN, Eriksson H, Kettle AJ J Biol Chem. 2011 Oct 28;286(43):37578-89. Epub 2011 Aug 31. PMID:21880720<ref>PMID:21880720</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3zs1" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Myeloperoxidase|Myeloperoxidase]] | *[[Myeloperoxidase|Myeloperoxidase]] | ||
*[[Sandbox WWC11|Sandbox WWC11]] | |||
== | == References == | ||
< | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Auchere | [[Category: Auchere F]] | ||
[[Category: Bernlind | [[Category: Bernlind A]] | ||
[[Category: Eriksson | [[Category: Eriksson H]] | ||
[[Category: Forbes | [[Category: Forbes LV]] | ||
[[Category: Gustavsson | [[Category: Gustavsson S]] | ||
[[Category: Jameson | [[Category: Jameson GN]] | ||
[[Category: Kettle | [[Category: Kettle AJ]] | ||
[[Category: Lundquist | [[Category: Lundquist S]] | ||
[[Category: Magon | [[Category: Magon NJ]] | ||
[[Category: Markgren | [[Category: Markgren PO]] | ||
[[Category: Norman | [[Category: Norman H]] | ||
[[Category: Schmidt | [[Category: Schmidt S]] | ||
[[Category: Senthilmohan | [[Category: Senthilmohan R]] | ||
[[Category: Sjogren | [[Category: Sjogren T]] | ||
[[Category: Svensson | [[Category: Svensson M]] | ||
[[Category: Tiden | [[Category: Tiden AK]] | ||
Latest revision as of 14:11, 20 December 2023
Human Myeloperoxidase inactivated by TX5Human Myeloperoxidase inactivated by TX5
Structural highlights
DiseasePERM_HUMAN Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5] FunctionPERM_HUMAN Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity. Publication Abstract from PubMedMyeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation. 2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.,Tiden AK, Sjogren T, Svensson M, Bernlind A, Senthilmohan R, Auchere F, Norman H, Markgren PO, Gustavsson S, Schmidt S, Lundquist S, Forbes LV, Magon NJ, Paton LN, Jameson GN, Eriksson H, Kettle AJ J Biol Chem. 2011 Oct 28;286(43):37578-89. Epub 2011 Aug 31. PMID:21880720[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||