title: Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations.
abstract: Human leukotriene A4 hydrolase (hLTA4H), which is the final and rate-limiting enzyme of arachidonic acid pathway, converts the unstable epoxide LTA4 to a proinflammatory lipid mediator LTB4 through its hydrolase function. The LTA4H is a bi-functional enzyme that also exhibits aminopeptidase activity with a preference over arginyl tripeptides. Various mutations including E271Q, R563A, and K565A have completely or partially abolished both the functions of this enzyme. The crystal structures with these mutations have not shown any structural changes to address the loss of functions. Molecular dynamics simulations of LTA4 and tripeptide complex structures with functional mutations were performed to investigate the structural and conformation changes that scripts the observed differences in catalytic functions. The observed protein-ligand hydrogen bonds and distances between the important catalytic components have correlated well with the experimental results. This study also confirms based on the structural observation that E271 is very important for both the functions as it holds the catalytic metal ion at its location for the catalysis and it also acts as N-terminal recognition residue during peptide binding. The comparison of binding modes of substrates revealed the structural changes explaining the importance of R563 and K565 residues and the required alignment of substrate at the active site. The results of this study provide valuable information to be utilized in designing potent hLTA4H inhibitors as anti-inflammatory agents.
authors: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center, Research Institute of Natural Science, Gyeongsang National University, Jinju, Republic of Korea.
authors: Sundarapandian
authors: S
authors: Thangapandian
authors: Shalini
authors: S
authors: John
authors: Prettina
authors: P
authors: Lazar
authors: Sun
authors: S
authors: Choi
authors: Keun Woo
authors: KW
authors: Lee
mesh_terms: D019943:Amino Acid Substitution; D002384:Catalysis; D020134:Catalytic Domain; D004851:Epoxide Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry* / Q000378:metabolism; D017572:Leukotriene A4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding
chemical_list: D018836:Inflammation Mediators; D017572:Leukotriene A4; D010455:Peptides; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase