Overview for MACiE Entry M0166

Version history

General Information

EC Number: (A member of the Hydrolases, Acting on ether bonds, Ether hydrolases)

Enzyme Name: leukotriene-A4 hydrolase

Biological Species: Homo sapiens (Human)

Catalytic Chain UniprotKB Accession Codes:

  • P09960 - Leukotriene A-4 hydrolase


Catalytic CATH Codes:

  • Unassigned Domain

Display structure information

Overall Reaction:

Image of leukotriene-A4

Image of water

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Image of leukotriene B4

leukotriene B4

Overall Comment: Leukotriene-A4 hydrolase is a bifunctional zinc metalloenzyme which performs epoxide hydrolysis (shown here) and also shows aminopeptidase activity from a common active site. The mechanism shown here is one of two possibilities. The alternative mechanism suggested includes the formation of an ester intermediate. In this scheme the zinc alone activates and opens the epoxide and a carboxylate of Glu271 attacks the substrate at C6 to form an ester intermediate. In a concerted SN2' reaction this ester can then be attacked by a hydroxo group at C12 and a negative charge can move along the conjugated triene system eventually leading to an alkyl-oxygen cleavage. However such cleavages of esters are rare reactions although not unknown [1].

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Stepwise Description of the Reaction

Step 1The oxygen of the oxirane ring in leukotriene A4 deprotonates a water molecule activated by Glu271.
Step 2The acidic oxirane ring collapses in a heterolysis.
Step 3Asp375 deprotonates a water molecule, which attacks the intermediate in a nucleophilic addition with attendant double bond rearrangement, producing the leukotriene B4 product.
Step 4Water deprotonates Asp375, regenerating the enzyme active site.

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Catalytic Residues Involved

Type Number Chain Location of Function
Glu 271 A Side Chain
Asp 375 A Side Chain

Metal Cofactors for M0166

Type Het group Number Chain
zinc ZN 701 A Overview


  1. P. C. Rudberg et al. (2002), J. Biol. Chem., 277, 1398-1404. Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.
    Medline: 11675384
  2. P. C. Rudberg et al. (2002), Proc. Natl Acad. Sci. USA, 99, 4215-4220. Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375.
    Medline: 11917124
  3. M. M. Thunnissen et al. (2001), Nat. Struct. Biol., 8, 131-135. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation.
    Medline: 11175901

Homologue information for M0166 (1hs6)

CSA Homologues

MACiE Homologues (within the PDB)

MACiE Homologues (within UniprotKB/SwissProt)

Links to this entry in other databases

Link to EC-PDB-SUM Link to PDB-SUM Link to RCSB PDB Link to PDBe Link to CSA
Link to MetaCyc Link to KEGG Link to BRENDA Link to ExplorENZ

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aminopeptidase activity (molecular function)
epoxide hydrolase activity (molecular function)
leukotriene-A4 hydrolase activity (molecular function)
binding (molecular function)
protein binding (molecular function)
nucleus (cellular component)
nucleolus (cellular component)
cytoplasm (cellular component)
cytosol (cellular component)
proteolysis (biological process)
prostanoid metabolic process (biological process)
inflammatory response (biological process)
peptidase activity (molecular function)
metallopeptidase activity (molecular function)
zinc ion binding (molecular function)
response to zinc ion (biological process)
leukotriene biosynthetic process (biological process)
peptide catabolic process (biological process)
response to peptide hormone (biological process)
metal ion binding (molecular function)
Type I pneumocyte differentiation (biological process)