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Product formation controlled by substrate dynamics in leukotriene A4 hydrolase.

Stsiapanava, Alena; Tholander, Fredrik; Kumar, Ramakrishnan B; Qureshi, Abdul Aziz; Niegowski, Damian; Hasan, Mahmudul LU ; Thunnissen, Marjolein LU ; Haeggström, Jesper Z and Rinaldo-Matthis, Agnes (2014) In Biochimica et Biophysica Acta 1844(2). p.439-446
Abstract
Leukotriene A4 hydrolase/aminopeptidase (LTA4H) (EC 3.3.2.6) is a bifunctional zinc metalloenzyme with both an epoxide hydrolase and an aminopeptidase activity. LTA4H from the African claw toad, Xenopus laevis (xlLTA4H) has been shown to, unlike the human enzyme, convert LTA4 to two enzymatic metabolites, LTB4 and another biologically active product Δ(6)-trans-Δ(8)-cis-LTB4 (5(S),12R-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid). In order to study the molecular aspect of the formation of this product we have characterized the structure and function of xlLTA4H. We solved the structure of xlLTA4H to a resolution of 2.3Å. It is a dimeric structure where each monomer has three domains with the active site in between the domains, similar... (More)
Leukotriene A4 hydrolase/aminopeptidase (LTA4H) (EC 3.3.2.6) is a bifunctional zinc metalloenzyme with both an epoxide hydrolase and an aminopeptidase activity. LTA4H from the African claw toad, Xenopus laevis (xlLTA4H) has been shown to, unlike the human enzyme, convert LTA4 to two enzymatic metabolites, LTB4 and another biologically active product Δ(6)-trans-Δ(8)-cis-LTB4 (5(S),12R-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid). In order to study the molecular aspect of the formation of this product we have characterized the structure and function of xlLTA4H. We solved the structure of xlLTA4H to a resolution of 2.3Å. It is a dimeric structure where each monomer has three domains with the active site in between the domains, similar as to the human structure. An important difference between the human and amphibian enzyme is the phenylalanine to tyrosine exchange at position 375. Our studies show that mutating F375 in xlLTA4H to tyrosine abolishes the formation of the LTB4 isomeric product Δ(6)-trans-Δ(8)-cis-LTB4. In an attempt to understand how one amino acid exchange leads to a new product profile as seen in the xlLTA4H, we performed a conformer analysis of the triene part of the substrate LTA4. Our results show that the Boltzmann distribution of substrate conformers correlates with the observed distribution of products. We suggest that the observed difference in product profile between the human and the xlLTA4H arises from different level of discrimination between substrate LTA4 conformers. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochimica et Biophysica Acta
volume
1844
issue
2
pages
439 - 446
publisher
Elsevier
external identifiers
  • pmid:24333438
  • wos:000330489000018
  • scopus:84896522815
ISSN
0006-3002
DOI
10.1016/j.bbapap.2013.12.003
language
English
LU publication?
yes
id
1c1173d0-8c76-48f0-a356-afdef68e8497 (old id 4223819)
date added to LUP
2014-02-05 17:41:29
date last changed
2017-01-01 05:41:59
@article{1c1173d0-8c76-48f0-a356-afdef68e8497,
  abstract     = {Leukotriene A4 hydrolase/aminopeptidase (LTA4H) (EC 3.3.2.6) is a bifunctional zinc metalloenzyme with both an epoxide hydrolase and an aminopeptidase activity. LTA4H from the African claw toad, Xenopus laevis (xlLTA4H) has been shown to, unlike the human enzyme, convert LTA4 to two enzymatic metabolites, LTB4 and another biologically active product Δ(6)-trans-Δ(8)-cis-LTB4 (5(S),12R-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid). In order to study the molecular aspect of the formation of this product we have characterized the structure and function of xlLTA4H. We solved the structure of xlLTA4H to a resolution of 2.3Å. It is a dimeric structure where each monomer has three domains with the active site in between the domains, similar as to the human structure. An important difference between the human and amphibian enzyme is the phenylalanine to tyrosine exchange at position 375. Our studies show that mutating F375 in xlLTA4H to tyrosine abolishes the formation of the LTB4 isomeric product Δ(6)-trans-Δ(8)-cis-LTB4. In an attempt to understand how one amino acid exchange leads to a new product profile as seen in the xlLTA4H, we performed a conformer analysis of the triene part of the substrate LTA4. Our results show that the Boltzmann distribution of substrate conformers correlates with the observed distribution of products. We suggest that the observed difference in product profile between the human and the xlLTA4H arises from different level of discrimination between substrate LTA4 conformers.},
  author       = {Stsiapanava, Alena and Tholander, Fredrik and Kumar, Ramakrishnan B and Qureshi, Abdul Aziz and Niegowski, Damian and Hasan, Mahmudul and Thunnissen, Marjolein and Haeggström, Jesper Z and Rinaldo-Matthis, Agnes},
  issn         = {0006-3002},
  language     = {eng},
  number       = {2},
  pages        = {439--446},
  publisher    = {Elsevier},
  series       = {Biochimica et Biophysica Acta},
  title        = {Product formation controlled by substrate dynamics in leukotriene A4 hydrolase.},
  url          = {http://dx.doi.org/10.1016/j.bbapap.2013.12.003},
  volume       = {1844},
  year         = {2014},
}