Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations.
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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3405069?pdf=render |
| _version_ | 1819261768727265280 |
|---|---|
| author | Sundarapandian Thangapandian Shalini John Prettina Lazar Sun Choi Keun Woo Lee |
| author_facet | Sundarapandian Thangapandian Shalini John Prettina Lazar Sun Choi Keun Woo Lee |
| author_sort | Sundarapandian Thangapandian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T19:47:03Z |
| format | Article |
| id | doaj.art-2cf83648986249e480687f611a173739 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T19:47:03Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2cf83648986249e480687f611a1737392022-12-21T17:33:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4106310.1371/journal.pone.0041063Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations.Sundarapandian ThangapandianShalini JohnPrettina LazarSun ChoiKeun Woo LeeHuman 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.http://europepmc.org/articles/PMC3405069?pdf=render |
| spellingShingle | Sundarapandian Thangapandian Shalini John Prettina Lazar Sun Choi Keun Woo Lee Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. PLoS ONE |
| title | Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. |
| title_full | Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. |
| title_fullStr | Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. |
| title_full_unstemmed | Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. |
| title_short | Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. |
| title_sort | structural origins for the loss of catalytic activities of bifunctional human lta4h revealed through molecular dynamics simulations |
| url | http://europepmc.org/articles/PMC3405069?pdf=render |
| work_keys_str_mv | AT sundarapandianthangapandian structuraloriginsforthelossofcatalyticactivitiesofbifunctionalhumanlta4hrevealedthroughmoleculardynamicssimulations AT shalinijohn structuraloriginsforthelossofcatalyticactivitiesofbifunctionalhumanlta4hrevealedthroughmoleculardynamicssimulations AT prettinalazar structuraloriginsforthelossofcatalyticactivitiesofbifunctionalhumanlta4hrevealedthroughmoleculardynamicssimulations AT sunchoi structuraloriginsforthelossofcatalyticactivitiesofbifunctionalhumanlta4hrevealedthroughmoleculardynamicssimulations AT keunwoolee structuraloriginsforthelossofcatalyticactivitiesofbifunctionalhumanlta4hrevealedthroughmoleculardynamicssimulations |