PDBsum entry 1hs6

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Hydrolase PDB id
Protein chain
610 a.a. *
_YB ×3
Waters ×551
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of leukotriene a4 hydrolase complexed with bestatin.
Structure: Leukotriene a-4 hydrolase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.95Å     R-factor:   0.185     R-free:   0.247
Authors: M.M.G.M.Thunnissen,P.N.Nordlund,J.Z.Haeggstrom
Key ref:
M.M.Thunnissen et al. (2001). Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol, 8, 131-135. PubMed id: 11175901 DOI: 10.1038/84117
24-Dec-00     Release date:   24-Jun-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P09960  (LKHA4_HUMAN) -  Leukotriene A-4 hydrolase
611 a.a.
610 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Leukotriene-A(4) hydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate + H2O = (6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate
+ H(2)O
= (6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   5 terms 
  Biological process     small molecule metabolic process   7 terms 
  Biochemical function     hydrolase activity     9 terms  


    Key reference    
DOI no: 10.1038/84117 Nat Struct Biol 8:131-135 (2001)
PubMed id: 11175901  
Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation.
M.M.Thunnissen, P.Nordlund, J.Z.Haeggström.
Leukotriene (LT) A(4) hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc enzyme that catalyzes the biosynthesis of LTB4, a potent lipid chemoattractant involved in inflammation, immune responses, host defense against infection, and PAF-induced shock. The high resolution crystal structure of LTA4H in complex with the competitive inhibitor bestatin reveals a protein folded into three domains that together create a deep cleft harboring the catalytic Zn(2+) site. A bent and narrow pocket, shaped to accommodate the substrate LTA(4), constitutes a highly confined binding region that can be targeted in the design of specific anti-inflammatory agents. Moreover, the structure of the catalytic domain is very similar to that of thermolysin and provides detailed insight into mechanisms of catalysis, in particular the chemical strategy for the unique epoxide hydrolase reaction that generates LTB(4).
  Selected figure(s)  
Figure 1.
Figure 1. Overall and domain structure of LTA4H. a, Ribbon diagram of the tertiary structure of LTA4H. The N-terminal domain is colored blue (residues 1 -207), the catalytic domain green (residues 208 -450) and the C-terminal domain red (residues 461 -610). A loop containing a highly conserved Pro-rich motif p451-G- -P-P-x-k-P-x-y460 ( , hydrophobic residues Phe, Tyr, Trp, Ile, Leu, Val, Met and Ala; capital letter, identical amino acids; small letter, conserved in chemistry) is shown in yellow. The figure was created using MolScript27, Glr (L. Esser and J. Deisenhofer, pers. comm.) and POV-Ray ( b, Stereo view of the superposition of the C trace of the catalytic domain (red) on thermolysin (blue). c, Stereo view of a 2F[o] - F[c] electron density map for the active site, including bestatin, contoured at 1.1 .
Figure 4.
Figure 4. Proposed reaction mechanism for the epoxide hydrolase activity of LTA4H. The carboxylate of LTA[4] is bound to Arg 563 and Lys 565. The catalytic Zn2+ acts as a Lewis acid and activates the epoxide to form a carbocation intermediate according to an S[N]1 reaction. Water is added at C12 in a stereospecific manner directed by Asp 375. The double bond geometry is controlled by the binding conformation of LTA[4].
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 131-135) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21508329 G.Kochan, T.Krojer, D.Harvey, R.Fischer, L.Chen, M.Vollmar, F.von Delft, K.L.Kavanagh, M.A.Brown, P.Bowness, P.Wordsworth, B.M.Kessler, and U.Oppermann (2011).
Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming.
  Proc Natl Acad Sci U S A, 108, 7745-7750.
PDB codes: 2yd0 3qnf
21493078 J.Su, Q.Wang, J.Feng, C.Zhang, D.Zhu, T.Wei, W.Xu, and L.Gu (2011).
Engineered Thermoplasma acidophilum factor F3 mimics human aminopeptidase N (APN) as a target for anticancer drug development.
  Bioorg Med Chem, 19, 2991-2996.
PDB code: 3q7j
21206090 S.F.Oh, P.S.Pillai, A.Recchiuti, R.Yang, and C.N.Serhan (2011).
Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation.
  J Clin Invest, 121, 569-581.  
21377770 S.Thangapandian, S.John, S.Sakkiah, and K.W.Lee (2011).
Pharmacophore-based virtual screening and Bayesian model for the identification of potential human leukotriene A4 hydrolase inhibitors.
  Eur J Med Chem, 46, 1593-1603.  
21478864 T.T.Nguyen, S.C.Chang, I.Evnouchidou, I.A.York, C.Zikos, K.L.Rock, A.L.Goldberg, E.Stratikos, and L.J.Stern (2011).
Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.
  Nat Struct Mol Biol, 18, 604-613.
PDB code: 3mdj
21258033 W.A.Peer (2011).
The role of multifunctional M1 metallopeptidases in cell cycle progression.
  Ann Bot, 107, 1171-1181.  
20706583 S.Vaiyapuri, S.C.Wagstaff, K.A.Watson, R.A.Harrison, J.M.Gibbins, and E.G.Hutchinson (2010).
Purification and functional characterisation of rhiminopeptidase A, a novel aminopeptidase from the venom of Bitis gabonica rhinoceros.
  PLoS Negl Trop Dis, 4, e796.  
20432426 X.Jiang, L.Zhou, Y.Wu, D.Wei, C.Sun, J.Jia, Y.Liu, and L.Lai (2010).
Modulating the substrate specificity of LTA4H aminopeptidase by using chemical compounds and small-molecule-guided mutagenesis.
  Chembiochem, 11, 1120-1128.  
19228697 C.Claperon, I.Banegas-Font, X.Iturrioz, R.Rozenfeld, B.Maigret, and C.Llorens-Cortes (2009).
Identification of threonine 348 as a residue involved in aminopeptidase a substrate specificity.
  J Biol Chem, 284, 10618-10626.  
19618939 D.R.Davies, B.Mamat, O.T.Magnusson, J.Christensen, M.H.Haraldsson, R.Mishra, B.Pease, E.Hansen, J.Singh, D.Zembower, H.Kim, A.S.Kiselyov, A.B.Burgin, M.E.Gurney, and L.J.Stewart (2009).
Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
  J Med Chem, 52, 4694-4715.
PDB codes: 3fts 3ftu 3ftv 3ftw 3ftx 3fty 3fu0 3fu3 3fu5 3fu6 3fud 3fue 3fuf 3fuh 3fui 3fuj 3fuk 3fum 3fun
19278651 G.Papai, M.K.Tripathi, C.Ruhlmann, S.Werten, C.Crucifix, P.A.Weil, and P.Schultz (2009).
Mapping the initiator binding Taf2 subunit in the structure of hydrated yeast TFIID.
  Structure, 17, 363-373.  
19622865 M.C.Fournié-Zaluski, H.Poras, B.P.Roques, Y.Nakajima, K.Ito, and T.Yoshimoto (2009).
Structure of aminopeptidase N from Escherichia coli complexed with the transition-state analogue aminophosphinic inhibitor PL250.
  Acta Crystallogr D Biol Crystallogr, 65, 814-822.
PDB code: 2zxg
19340413 M.Decker, M.Arand, and A.Cronin (2009).
Mammalian epoxide hydrolases in xenobiotic metabolism and signalling.
  Arch Toxicol, 83, 297-318.  
19819873 M.Maruyama, N.Arisaka, Y.Goto, Y.Ohsawa, H.Inoue, H.Fujiwara, A.Hattori, and M.Tsujimoto (2009).
Histidine 379 of human laeverin/aminopeptidase Q, a nonconserved residue within the exopeptidase motif, defines its distinctive enzymatic properties.
  J Biol Chem, 284, 34692-34702.  
19244215 M.W.Buczynski, D.S.Dumlao, and E.A.Dennis (2009).
Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology.
  J Lipid Res, 50, 1015-1038.  
17876832 B.Nocek, R.Mulligan, M.Bargassa, F.Collart, and A.Joachimiak (2008).
Crystal structure of aminopeptidase N from human pathogen Neisseria meningitidis.
  Proteins, 70, 273-279.
PDB code: 2gtq
18539590 C.Bauvois, L.Jacquamet, A.L.Huston, F.Borel, G.Feller, and J.L.Ferrer (2008).
Crystal structure of the cold-active aminopeptidase from Colwellia psychrerythraea, a close structural homologue of the human bifunctional leukotriene A4 hydrolase.
  J Biol Chem, 283, 23315-23325.
PDB code: 3cia
17803194 R.Axton, J.A.Wallis, H.Taylor, M.Hanks, and L.M.Forrester (2008).
Aminopeptidase O contains a functional nucleolar localization signal and is implicated in vascular biology.
  J Cell Biochem, 103, 1171-1182.  
19090987 S.Y.Chai, H.R.Yeatman, M.W.Parker, D.B.Ascher, P.E.Thompson, H.T.Mulvey, and A.L.Albiston (2008).
Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase.
  BMC Neurosci, 9, S14.  
18523486 S.Ye, S.Y.Chai, R.A.Lew, D.B.Ascher, C.J.Morton, M.W.Parker, and A.L.Albiston (2008).
Identification of modulating residues defining the catalytic cleft of insulin-regulated aminopeptidase.
  Biochem Cell Biol, 86, 251-261.  
17900701 A.L.Albiston, G.R.Peck, H.R.Yeatman, R.Fernando, S.Ye, and S.Y.Chai (2007).
Therapeutic targeting of insulin-regulated aminopeptidase: heads and tails?
  Pharmacol Ther, 116, 417-427.  
17429823 B.M.McArdle, and R.J.Quinn (2007).
Identification of protein fold topology shared between different folds inhibited by natural products.
  Chembiochem, 8, 788-798.  
18041998 C.Whatling, W.McPheat, and M.Herslöf (2007).
The potential link between atherosclerosis and the 5-lipoxygenase pathway: investigational agents with new implications for the cardiovascular field.
  Expert Opin Investig Drugs, 16, 1879-1893.  
17476590 K.S.Hui (2007).
Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration.
  Neurochem Res, 32, 2062-2071.  
17974014 V.L.Pham, M.S.Cadel, C.Gouzy-Darmon, C.Hanquez, M.C.Beinfeld, P.Nicolas, C.Etchebest, and T.Foulon (2007).
Aminopeptidase B, a glucagon-processing enzyme: site directed mutagenesis of the Zn2+-binding motif and molecular modelling.
  BMC Biochem, 8, 21.  
17932029 Y.Goto, A.Hattori, S.Mizutani, and M.Tsujimoto (2007).
Asparatic Acid 221 Is Critical in the Calcium-induced Modulation of the Enzymatic Activity of Human Aminopeptidase A.
  J Biol Chem, 282, 37074-37081.  
16938892 A.Addlagatta, L.Gay, and B.W.Matthews (2006).
Structure of aminopeptidase N from Escherichia coli suggests a compartmentalized, gated active site.
  Proc Natl Acad Sci U S A, 103, 13339-13344.
PDB codes: 2hpo 2hpt
16885166 K.Ito, Y.Nakajima, Y.Onohara, M.Takeo, K.Nakashima, F.Matsubara, T.Ito, and T.Yoshimoto (2006).
Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition.
  J Biol Chem, 281, 33664-33676.
PDB codes: 2dq6 2dqm
16611635 L.Chávez-Gutiérrez, E.Matta-Camacho, J.Osuna, E.Horjales, P.Joseph-Bravo, B.Maigret, and J.L.Charli (2006).
Homology modeling and site-directed mutagenesis of pyroglutamyl peptidase II. Insights into omega-versus aminopeptidase specificity in the M1 family.
  J Biol Chem, 281, 18581-18590.  
16892380 S.Weik, T.Luksch, A.Evers, J.Böttcher, C.A.Sotriffer, A.Hasilik, H.G.Löffler, G.Klebe, and J.Rademann (2006).
The potential of P1 site alterations in peptidomimetic protease inhibitors as suggested by virtual screening and explored by the use of C-C-coupling reagents.
  ChemMedChem, 1, 445-457.  
15687497 A.Díaz-Perales, V.Quesada, L.M.Sánchez, A.P.Ugalde, M.F.Suárez, A.Fueyo, and C.López-Otín (2005).
Identification of human aminopeptidase O, a novel metalloprotease with structural similarity to aminopeptidase B and leukotriene A4 hydrolase.
  J Biol Chem, 280, 14310-14317.  
15748538 A.Reaux-Le Goazigo, X.Iturrioz, C.Fassot, C.Claperon, B.P.Roques, and C.Llorens-Cortes (2005).
Role of angiotensin III in hypertension.
  Curr Hypertens Rep, 7, 128-134.  
16024909 F.Tholander, F.Kull, E.Ohlson, J.Shafqat, M.M.Thunnissen, and J.Z.Haeggström (2005).
Leukotriene A4 hydrolase, insights into the molecular evolution by homology modeling and mutational analysis of enzyme from Saccharomyces cerevisiae.
  J Biol Chem, 280, 33477-33486.  
15748653 J.W.Newman, C.Morisseau, and B.D.Hammock (2005).
Epoxide hydrolases: their roles and interactions with lipid metabolism.
  Prog Lipid Res, 44, 1.  
15686482 L.Chávez-Gutiérrez, J.Bourdais, G.Aranda, M.A.Vargas, E.Matta-Camacho, F.Ducancel, L.Segovia, P.Joseph-Bravo, and J.L.Charli (2005).
A truncated isoform of pyroglutamyl aminopeptidase II produced by exon extension has dominant-negative activity.
  J Neurochem, 92, 807-817.  
15184127 A.L.Huston, B.Methe, and J.W.Deming (2004).
Purification, characterization, and sequencing of an extracellular cold-active aminopeptidase produced by marine psychrophile Colwellia psychrerythraea strain 34H.
  Appl Environ Microbiol, 70, 3321-3328.  
15339917 J.Z.Haeggström (2004).
Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis.
  J Biol Chem, 279, 50639-50642.  
15078870 P.C.Rudberg, F.Tholander, M.Andberg, M.M.Thunnissen, and J.Z.Haeggström (2004).
Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates.
  J Biol Chem, 279, 27376-27382.
PDB code: 1sqm
15263000 R.Rozenfeld, L.Muller, S.El Messari, and C.Llorens-Cortes (2004).
The C-terminal domain of aminopeptidase A is an intramolecular chaperone required for the correct folding, cell surface expression, and activity of this monozinc aminopeptidase.
  J Biol Chem, 279, 43285-43295.  
14515987 M.A.Koch, R.Breinbauer, and H.Waldmann (2003).
Protein structure similarity as guiding principle for combinatorial library design.
  Biol Chem, 384, 1265-1272.  
12773375 M.Arand, B.M.Hallberg, J.Zou, T.Bergfors, F.Oesch, M.J.van der Werf, Bont, T.A.Jones, and S.L.Mowbray (2003).
Structure of Rhodococcus erythropolis limonene-1,2-epoxide hydrolase reveals a novel active site.
  EMBO J, 22, 2583-2592.
PDB codes: 1nu3 1nww
14674752 R.Rozenfeld, X.Iturrioz, M.Okada, B.Maigret, and C.Llorens-Cortes (2003).
Contribution of molecular modeling and site-directed mutagenesis to the identification of a new residue, glutamate 215, involved in the exopeptidase specificity of aminopeptidase A.
  Biochemistry, 42, 14785-14793.  
12865451 X.Chen, N.Li, S.Wang, N.Wu, J.Hong, X.Jiao, M.J.Krasna, D.G.Beer, and C.S.Yang (2003).
Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin.
  J Natl Cancer Inst, 95, 1053-1061.  
11917124 P.C.Rudberg, F.Tholander, M.M.Thunnissen, B.Samuelsson, and J.Z.Haeggstrom (2002).
Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375.
  Proc Natl Acad Sci U S A, 99, 4215-4220.
PDB code: 1gw6
12042323 R.Rozenfeld, X.Iturrioz, B.Maigret, and C.Llorens-Cortes (2002).
Contribution of molecular modeling and site-directed mutagenesis to the identification of two structural residues, Arg-220 and Asp-227, in aminopeptidase A.
  J Biol Chem, 277, 29242-29252.  
12355480 T.Shimizu, K.Tani, K.Hase, H.Ogawa, L.Huang, F.Shinomiya, and S.Sone (2002).
CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis.
  Arthritis Rheum, 46, 2330-2338.  
11729303 C.D.Funk (2001).
Prostaglandins and leukotrienes: advances in eicosanoid biology.
  Science, 294, 1871-1875.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.