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通过促进溶剂进入来调节 D-氨基酸氧化酶（DAAO）的底物特异性。

Modulating D-amino acid oxidase (DAAO) substrate specificity through facilitated solvent access.

机构信息

Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Stippeneng WE, Wageningen, The Netherlands.

Tunneling Group, Biotechnology Centre, Silesian University of Technology, ul. Krzywoustego, Gliwice, Poland.

出版信息

PLoS One. 2018 Jun 15;13(6):e0198990. doi: 10.1371/journal.pone.0198990. eCollection 2018.

DOI:10.1371/journal.pone.0198990
PMID:29906280
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6003678/
Abstract

D-amino acid oxidase (DAAO) degrades D-amino acids to produce α-ketoacids, hydrogen peroxide and ammonia. DAAO has often been investigated and engineered for industrial and clinical applications. We combined information from literature with a detailed analysis of the structure to engineer mammalian DAAOs. The structural analysis was complemented with molecular dynamics simulations to characterize solvent accessibility and product release mechanisms. We identified non-obvious residues located on the loops on the border between the active site and the secondary binding pocket essential for pig and human DAAO substrate specificity and activity. We engineered DAAOs by mutating such critical residues and characterised the biochemical activity of the resulting variants. The results highlight the importance of the selected residues in modulating substrate specificity, product egress and enzyme activity, suggesting further steps of DAAO re-engineering towards desired clinical and industrial applications.

摘要

D-氨基酸氧化酶（DAAO）将 D-氨基酸降解为α-酮酸、过氧化氢和氨。DAAO 经常被研究和工程化用于工业和临床应用。我们结合文献信息和对结构的详细分析来工程化哺乳动物 DAAO。结构分析辅以分子动力学模拟，以表征溶剂可及性和产物释放机制。我们鉴定了位于活性位点和二级结合口袋边界上的环上的非明显残基，这些残基对于猪和人 DAAO 的底物特异性和活性至关重要。我们通过突变这些关键残基来工程化 DAAO，并对所得变体的生化活性进行了表征。结果突出了所选残基在调节底物特异性、产物流出和酶活性方面的重要性，这表明朝着期望的临床和工业应用进一步对 DAAO 进行重新工程化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/75ba809074e6/pone.0198990.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/b38bf73cc1d6/pone.0198990.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/a7799a987861/pone.0198990.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/3b00f779fdef/pone.0198990.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/d7913e6780bc/pone.0198990.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/137f5200a31c/pone.0198990.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/568785981504/pone.0198990.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/75ba809074e6/pone.0198990.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/b38bf73cc1d6/pone.0198990.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/a7799a987861/pone.0198990.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/3b00f779fdef/pone.0198990.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/d7913e6780bc/pone.0198990.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/137f5200a31c/pone.0198990.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/568785981504/pone.0198990.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6296/6003678/75ba809074e6/pone.0198990.g007.jpg

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