PDBsum entry 5bpp

Hydrolase/hydrolase inhibitor

PDB id: 5bpp

Contents

Protein chain

607 a.a.

Ligands

ACT

A4Z

Metals

_ZN

_YB ×3

Waters ×243

PDB id:

5bpp

Name:

Hydrolase/hydrolase inhibitor

Title:

Structure of human leukotriene a4 hydrolase in complex with inhibitor 4az

Structure:

Leukotriene a-4 hydrolase. Chain: a. Synonym: lta-4 hydrolase,leukotriene a(4) hydrolase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lta4h, lta4. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.03Å R-factor: 0.183 R-free: 0.224

Authors:

J.Huang,N.N.Dong,Q.Xiao,P.Y.Ou,D.Wu,W.Q.Lu

Key ref:

Q.Xiao et al. (2016). Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H. Sci Rep, 6, 25298. PubMed id: 27126280 DOI: 10.1038/srep25298

Date:

28-May-15 Release date: 10-Aug-16

Protein chain

P09960  (LKHA4_HUMAN) -  Leukotriene A-4 hydrolase from Homo sapiens

Seq: 611 a.a.

Struc: 607 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.3.2.6 - leukotriene-A4 hydrolase.
• Reaction: leukotriene A4 + H2O = leukotriene B4
• Cofactor: Zn(2+)
• Enzyme class 3: E.C.3.4.11.4 - tripeptide aminopeptidase.
• Reaction: Release of a N-terminal residue from a tripeptide.
• Cofactor: Zn(2+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/srep25298

Sci Rep 6:25298 (2016)

PubMed id: 27126280

Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.

Q.Xiao, N.Dong, X.Yao, D.Wu, Y.Lu, F.Mao, J.Zhu, J.Li, J.Huang, A.Chen, L.Huang, X.Wang, G.Yang, G.He, Y.Xu, W.Lu.

ABSTRACT

Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI.