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6enb

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Revision as of 06:54, 24 October 2018

LTA4 hydrolase (E297Q) mutant in complex with Pro-Gly-Pro peptide

Structural highlights

6enb is a 2 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:	LTA4H, LTA4 (HUMAN)
Activity:	Leukotriene-A(4) hydrolase, with EC number 3.3.2.6
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential. Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.

Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors.,Numao S, Hasler F, Laguerre C, Srinivas H, Wack N, Jager P, Schmid A, Osmont A, Rothlisberger P, Houguenade J, Bergsdorf C, Dawson J, Carte N, Hofmann A, Markert C, Hardaker L, Billich A, Wolf RM, Penno CA, Bollbuck B, Miltz W, Rohn TA Sci Rep. 2017 Oct 19;7(1):13591. doi: 10.1038/s41598-017-13490-1. PMID:29051536^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Numao S, Hasler F, Laguerre C, Srinivas H, Wack N, Jager P, Schmid A, Osmont A, Rothlisberger P, Houguenade J, Bergsdorf C, Dawson J, Carte N, Hofmann A, Markert C, Hardaker L, Billich A, Wolf RM, Penno CA, Bollbuck B, Miltz W, Rohn TA. Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors. Sci Rep. 2017 Oct 19;7(1):13591. doi: 10.1038/s41598-017-13490-1. PMID:29051536 doi:http://dx.doi.org/10.1038/s41598-017-13490-1

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6enb"

Categories: Human | Srinivas, H | Hydrolase | Lta4h | Substrate

@@ Line 3: / Line 3: @@
 <StructureSection load='6enb' size='340' side='right' caption='[[6enb]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6enb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ENB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ENB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6enb]] is a 2 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=6ENB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ENB FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LTA4H, LTA4 ([http://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/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] </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=6enb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6enb OCA], [http://pdbe.org/6enb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6enb RCSB], [http://www.ebi.ac.uk/pdbsum/6enb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6enb ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Srinivas, H]]
 [[Category: Hydrolase]]
 [[Category: Lta4h]]
 [[Category: Substrate]]

6enb

From Proteopedia

Revision as of 06:54, 24 October 2018

LTA4 hydrolase (E297Q) mutant in complex with Pro-Gly-Pro peptide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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