1H19

STRUCTURE OF [E271Q]LEUKOTRIENE A4 HYDROLASE

Summary for 1H19

• Entry DOI: 10.2210/pdb1h19/pdb
• Related: 1GW6 1HS6
• Descriptor: LEUKOTRIENE A-4 HYDROLASE, ZINC ION, YTTERBIUM (III) ION, ... (6 entities in total)
• Functional Keywords: hydrolase, alpha-beta protein, leukotriene biosynthesis, metalloprotease
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 69730.57

Authors

Rudberg, P.C.,Tholander, F.,Thunnissen, M.M.G.M.,Haeggstrom, J.Z. (deposition date: 2002-07-04, release date: 2002-08-08, Last modification date: 2023-12-13)

Primary citation

Rudberg, P.C.,Tholander, F.,Thunnissen, M.M.G.M.,Haeggstrom, J.Z.
Leukotriene A4 Hydrolase/Aminopeptidase, Glutamate 271 is a Catalyticresidue with Specific Roles in Two Distinct Enzyme Mechanisms
J.Biol.Chem., 277:1398-, 2002

PubMed Abstract: Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively.

PubMed: 11675384
DOI: 10.1074/JBC.M106577200

Experimental method

X-RAY DIFFRACTION (2.1 Å)