PDBsum entry 6o5h

Hydrolase

PDB id: 6o5h

Contents

Protein chains

607 a.a.

Ligands

LNJ ×3

Metals

_ZN ×3

Waters ×356

PDB id:

6o5h

Name:

Hydrolase

Title:

The effect of modifier structure on the activation of leukotriene a4 hydrolase aminopeptidase activity.

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lta4h, lta4. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.84Å R-factor: 0.219 R-free: 0.229

Authors:

S.M.Noble,K.H.Lee,M.Paige

Key ref:

K.H.Lee et al. (2019). Effect of Modifier Structure on the Activation of Leukotriene A₄ Hydrolase Aminopeptidase Activity. J Med Chem, 62, 10605-10616. PubMed id: 31751136 DOI: 10.1021/acs.jmedchem.9b00663

Date:

03-Mar-19 Release date: 04-Dec-19

Protein chains

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

leukotriene A4 + H2O (Bound ligand (Het Group name = LNJ) matches with 41.94% similarity) = 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: 10.1021/acs.jmedchem.9b00663

J Med Chem 62:10605-10616 (2019)

PubMed id: 31751136

Effect of Modifier Structure on the Activation of Leukotriene A₄ Hydrolase Aminopeptidase Activity.

K.H.Lee, G.Petruncio, A.Shim, M.Burdick, Z.Zhang, Y.M.Shim, S.M.Noble, M.Paige.

ABSTRACT

Activation of the leukotriene A₄ hydrolase (LTA₄H) aminopeptidase (AP) activity with 4-methoxydiphenylmethane (4MDM) promoted resolution of neutrophil infiltration in a murine cigarette smoke-induced model for emphysematous chronic obstructive pulmonary disease. Recently, 4-(4-benzylphenyl)thiazol-2-amine (ARM1) was published as a ligand for LTA₄H with potential anti-inflammatory properties. To investigate the effect of modifier structure on enzyme kinetics of LTA₄H, a series of analogues bearing structural features of ARM1 and 4MDM were synthesized using trifluoroborate Suzuki coupling reactions. Following, the 2.8 Å X-ray crystal structure of LTA₄H complexed with 4-OMe-ARM1, a 4MDM-ARM1 hybrid molecule, was determined. Kinetic analysis showed that ARM1 and related analogues lowered affinity for the enzyme-substrate complex, resulting in a change of mechanism from hyperbolic mixed predominately catalytic activation (HMx(Sp < Ca)A) as observed for 4MDM to a predominately specific activation (HMx(Sp > Ca)A) mechanism. 4-OMe-ARM1 was then shown to dose responsively reduce LTB₄ production in human neutrophils.