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==Substrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activity== | ==Substrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activity== | ||
<StructureSection load='7llq' size='340' side='right'caption='[[7llq]]' scene=''> | <StructureSection load='7llq' size='340' side='right'caption='[[7llq]], [[Resolution|resolution]] 2.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LLQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[7llq]] is a 3 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=7LLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LLQ FirstGlance]. <br> | ||
</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=7llq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7llq OCA], [https://pdbe.org/7llq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7llq RCSB], [https://www.ebi.ac.uk/pdbsum/7llq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7llq ProSAT]</span></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]] 2.85Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=28T:1-{4-OXO-4-[(2S)-PYRROLIDIN-2-YL]BUTANOYL}-L-PROLINE'>28T</scene>, <scene name='pdbligand=N0Y:1-benzyl-4-methoxybenzene'>N0Y</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=7llq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7llq OCA], [https://pdbe.org/7llq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7llq RCSB], [https://www.ebi.ac.uk/pdbsum/7llq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7llq ProSAT]</span></td></tr> | |||
</table> | </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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H. | |||
Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.,Lee KH, Ali NF, Lee SH, Zhang Z, Burdick M, Beaulac ZJ, Petruncio G, Li L, Xiang J, Chung EM, Foreman KW, Noble SM, Shim YM, Paige M Sci Rep. 2022 Jun 8;12(1):9443. doi: 10.1038/s41598-022-13238-6. PMID:35676292<ref>PMID:35676292</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7llq" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Leukotriene A4 Hydrolase|Leukotriene A4 Hydrolase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lee KH]] | [[Category: Lee KH]] | ||
Latest revision as of 18:53, 18 October 2023
Substrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activitySubstrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activity
Structural highlights
FunctionLKHA4_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] Publication Abstract from PubMedThe aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H. Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.,Lee KH, Ali NF, Lee SH, Zhang Z, Burdick M, Beaulac ZJ, Petruncio G, Li L, Xiang J, Chung EM, Foreman KW, Noble SM, Shim YM, Paige M Sci Rep. 2022 Jun 8;12(1):9443. doi: 10.1038/s41598-022-13238-6. PMID:35676292[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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