Insights into the structural determinants of substrate specificity and activity in mouse aldehyde oxidases

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• 作者：Nuno M. F. S. A. Cerqueira (1)
  Catarina Coelho (2)
  Nat茅rcia F. Br谩s (1)
  Pedro A. Fernandes (1)
  Enrico Garattini (3)
  Mineko Terao (3)
  Maria Jo茫o Rom茫o (2)
  Maria Jo茫o Ramos (1)
  
• 关键词：Mouse aldehyde oxidases ; Molybdo ; flavoenzyme ; Homology modeling ; Molecular dynamics
• 刊名：Journal of Biological Inorganic Chemistry
• 出版年：2015
• 出版时间：March 2015
• 年：2015
• 卷：20
• 期：2
• 页码：209-217
• 全文大小：1,655 KB
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• 作者单位：Nuno M. F. S. A. Cerqueira (1)
  Catarina Coelho (2)
  Nat茅rcia F. Br谩s (1)
  Pedro A. Fernandes (1)
  Enrico Garattini (3)
  Mineko Terao (3)
  Maria Jo茫o Rom茫o (2)
  Maria Jo茫o Ramos (1)
  
  1. UCIBIO@REQUIMTE, Departamento de Qu铆mica e Bioqu铆mica, Faculdade de Ci锚ncias, Universidade do Porto, 4169-007, Porto, Portugal
  2. UCIBIO@REQUIMTE, Departamento de Qu铆mica, Faculdade de Ci锚ncias e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal
  3. Laboratory of Molecular Biology, IRCCS/Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156, Milano, Italy
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Microbiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1327

文摘

In this work, a combination of homology modeling and molecular dynamics (MD) simulations was used to investigate the factors that modulate substrate specificity and activity of the mouse AOX isoforms: mAOX1, mAOX2 (previously mAOX3l1), mAOX3 and mAOX4. The results indicate that the AOX isoform structures are highly preserved and even more conserved than the corresponding amino acid sequences. The only differences are at the protein surface and substrate-binding site region. The substrate-binding site of all isoforms consists of two regions: the active site, which is highly conserved among all isoforms, and a isoform-specific region located above. We predict that mAOX1 accepts a broader range of substrates of different shape, size and nature relative to the other isoforms. In contrast, mAOX4 appears to accept a more restricted range of substrates. Its narrow and hydrophobic binding site indicates that it only accepts small hydrophobic substrates. Although mAOX2 and mAOX3 are very similar to each other, we propose the following pairs of overlapping substrate specificities: mAOX2/mAOX4 and mAOX3/mAXO1. Based on these considerations, we propose that the catalytic activity between all isoforms should be similar but the differences observed in the binding site might influence the substrate specificity of each enzyme. These results also suggest that the presence of several AOX isoforms in mouse allows them to oxidize more efficiently a wider range of substrates. This contrasts with the same or other organisms that only express one isoform and are less efficient or incapable of oxidizing the same type of substrates.