Leukotriene A4 Hydrolase

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[[Image:2xpz.jpg|left|200px|thumb|Crystal Structure of Leukotriene A4 Hydrolase [[2xpz]]]]
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<StructureSection load='' size='350' side='right' caption='Human leukotriene A4 Hydrolase complex with bestatin, acetate, imidazole, Yb+3 (green) and Zn+2 (grey) ions (PDB entry [[1hs6]])' scene='43/433034/Cv/1'>
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{{STRUCTURE_2xpz| PDB=2xpz | SIZE=300| SCENE=Subtilisin/Cv/1 |right|CAPTION=Leukotriene A4 Hydrolase [[2xpz]] }}
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== Function ==
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[[Leukotriene A4 Hydrolase]] (LTA4H) is an aminopeptidase which converts leukotriene A4 to leukotriene B4 as part of the arachidonic acid metabolism<ref>PMID:24771855</ref> . LTA4H is a bifunctional Zn+2 enzyme.
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[[Leukotriene A4 Hydrolase]] (LTA4H) is an aminopeptidase which converts leukotriene A4 to leukotriene B4 as part of the arachidonic acid metabolism. The images at the left and at the right correspond to one representative LTA4H, ''i.e.'' the crystal structure of yeast Leukotriene A4 Hydrolase ([[2xpz]]).
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== Relevance ==
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LTA4H inhibitors have potential in targeting chronic, autoimmune-driven inflammation<ref>PMID:19876785</ref> .
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{{TOC limit|limit=2}}
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== Disease ==
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<br />
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Mutations in LTA4H are linked to susceptibility to asthma and to cardiovascular disease.
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== Structural highlights ==
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LTA4H structure shows <scene name='43/433034/Cv/10'>3 domains: N-terminal, catalytic and C-terminal</scene>. The catalytic domain is made of 2 lobes: an α-helical one and an α/β one. The <scene name='43/433034/Cv/11'>catalytic site</scene> is located between the 2 lobes and <scene name='43/433034/Cv/12'>contains a Zn+2 ion</scene><ref>PMID:11175901</ref>. Water molecules shown as red spheres.
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<scene name='43/433034/Cv/8'>1st Yb coordination site</scene>.
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<scene name='43/433034/Cv/9'>2nd Yb coordination site</scene>.
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</StructureSection>
== 3D Structures of Leukotriene A4 Hydrolase ==
== 3D Structures of Leukotriene A4 Hydrolase ==
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[[2xpz]] – yLTA4H – yeast<br />
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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[[1xpy]] – yLTA4H+glutathione <br />
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{{#tree:id=OrganizedByTopic|openlevels=0|
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[[2xq0]] – yLTA4H+bestatin<br />
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[[1sqm]], [[1gw6]], [[1h19]] - hLTA4H (mutant)<br />
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* LTA4H
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[[3fh5]], [[3fh7]], [[3fh8]], [[3fhe]], [[3ftz]], [[3ful]], [[3ftv]], [[3ftw]], [[3fty]], [[3fu0]], [[3fu3]], [[3fu5]], [[3fu6]], [[3fud]], [[3fue]], [[3fuf]], [[3fuh]], [[3fui]], [[3fuj]], [[3fuk]], [[3fum]], [[3fun]], [[3b7r]], [[2r59]], [[3cho]], [[3chp]], [[3chq]], [[3chr]], [[3chs]], [[2vj8]] – hLA4H+inhibitor<br />
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[[3ftz]], [[3ftv]], [[3ftw]], [[3ftx]], [[3fui]] - hLTA4H+aniline derivative<br />
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**[[4rvb]], [[5fwq]] - hLTA4H – human<br />
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[[3fts]], [[3ftu]] - hLTA4H+resveratrol derivative<br />
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**[[1sqm]], [[1gw6]], [[1h19]] - hLTA4H (mutant) <br />
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[[3fty]], [[3fu0]] - hLTA4H+pyridine derivative<br />
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**[[1xpy]], [[2xpy]], [[2xpz]] – yLTA4H – yeast<br />
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[[3fu3]], [[3fu5]], [[3fu6]], [[3fud]] - hLTA4H+thio derivative<br />
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[[3fue]], [[3fuf]], [[3fuh]] - hLTA4H+bestatin+indole derivative<br />
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* LTA4H + inhibitor
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[[3fuj]], [[3fuk]] - hLTA4H+indole derivative<br />
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[[3b7r]], [[3cho]], [[3chp]], [[3chq]], [[3chr]], [[3chs]] - hLTA4H+inhibitor<br />
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**[[3fh5]], [[3fh7]], [[3fh8]], [[3fhe]], [[3ful]], [[3fum]], [[3fun]] - hLTA4H+pyrrolidine inhibitor
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[[3b7u]] - hLTA4H+kelatorphan<br />
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**[[1hs6]] - hLTA4H+bestatin<br />
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[[2vj8]] - hLTA4H+hydroxamic acid<br />
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**[[3ftz]], [[3ftv]], [[3ftw]], [[3ftx]], [[3fui]] - hLTA4H+aniline derivative<br />
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[[3b7s]], [[3b7t]] - hLTA4H (mutant)+tripeptide<br />
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**[[3fts]], [[3ftu]] - hLTA4H+resveratrol derivative<br />
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[[1hs6]] - hLTA4H+bestatin<br />
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**[[3fty]], [[3fu0]] - hLTA4H+pyridine derivative<br />
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**[[3fu3]], [[3fu5]], [[3fu6]], [[3fud]] - hLTA4H+thio derivative<br />
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**[[3fue]], [[3fuf]], [[3fuh]] - hLTA4H+bestatin+indole derivative<br />
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**[[3fuj]], [[3fuk]] - hLTA4H+indole derivative<br />
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**[[3b7r]], [[3cho]], [[3chp]], [[3chq]], [[3chr]], [[3chs]], [[2r59]], [[3u9w]], [[4r7l]], [[4rsy]], [[5aen]], [[5bpp]], [[6enc]], [[6end]], [[7auz]], [[7av0]], [[7av1]], [[7av2]], [[8ava]], [[8awh]] - hLTA4H+inhibitor<br />
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**[[3b7u]] - hLTA4H+kelatorphan <br />
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**[[2vj8]] - hLTA4H+hydroxamic acid<br />
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**[[4dpr]] – hLTA4H + captopril<br />
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**[[4ms6]], [[7kze]], [[7llq]] - hLTA4H +tripeptide analog <br />
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**[[4l2l]] - hLTA4H + thiazol derivative<br />
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**[[4mkt]] - hLTA4H +tripeptide analog + thiazol derivative<br />
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**[[3b7s]], [[3b7t]], [[6enb]] - hLTA4H (mutant)+tripeptide<br />
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**[[6o5h]] – hLTA4H + modifier<br />
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**[[4gaa]] - LTA4H+bestatin – frog<br />
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**[[2xq0]] – yLTA4H+bestatin<br />
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}}
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== References ==
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<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Human leukotriene A4 Hydrolase complex with bestatin, acetate, imidazole, Yb+3 (green) and Zn+2 (grey) ions (PDB entry 1hs6)

Drag the structure with the mouse to rotate

3D Structures of Leukotriene A4 Hydrolase

Updated on 18-June-2023

References

  1. ↑ Paige M, Wang K, Burdick M, Park S, Cha J, Jeffery E, Sherman N, Shim YM. Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema. J Immunol. 2014 Jun 1;192(11):5059-68. doi: 10.4049/jimmunol.1400452. Epub 2014, Apr 25. PMID:24771855 doi:http://dx.doi.org/10.4049/jimmunol.1400452
  2. ↑ Fourie AM. Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase. Curr Opin Investig Drugs. 2009 Nov;10(11):1173-82. PMID:19876785
  3. ↑ Thunnissen MM, Nordlund P, Haeggstrom JZ. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol. 2001 Feb;8(2):131-5. PMID:11175901 doi:10.1038/84117

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Michal Harel, Alexander Berchansky, Joel L. Sussman

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