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Title 

Integration of inhibition kinetics and molecular dynamics simulations: a urea-mediated folding study on acetaldehyde dehydrogenase 1

Authors 

Y XuJinhyuk LeeZ R LuH MuQ ZhangY D Park

Publisher 

Humana Press

Issue Date 

2016

Citation 

Applied Biochemistry and Biotechnology, vol. 179, no. 6, pp. 1101-1114

Keywords 

Acetaldehyde dehydrogenase 1InhibitionKineticsMolecular dynamicsSimulationsUrea

Abstract 

Understanding the mechanism of acetaldehyde dehydrogenase 1 (ALDH1) folding is important because this enzyme is directly involved in several types of cancers and other diseases. We investigated the urea-mediated unfolding of ALDH1 by integrating kinetic inhibition studies with computational molecular dynamics (MD) simulations. Conformational changes in the enzyme structure were also analyzed using intrinsic and 1-anilinonaphthalene-8-sulfonate (ANS)-binding fluorescence measurements. Kinetic studies revealed that the direct binding of urea to ALDH1 induces inactivation of ALDH1 in a manner of mixed-type inhibition. Tertiary structural changes associated with regional hydrophobic exposure of the active site were observed. The urea binding regions on ALDH1 were predicted by docking simulations and were partly shared with active site residues of ALDH1 and with interface residues of the oligomerization domain for tetramer formation. The docking results suggest that urea prevents formation of the ALDH1 normal shape for the tetramer state as well as entrance of the substrate into the active site. Our study provides insight into the structural changes that accompany urea-mediated unfolding of ALDH1 and the catalytic role associated with conformational changes.

ISSN 

0273-2289

Link 

http://dx.doi.org/10.1007/s12010-016-2052-5

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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