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Integration of inhibition kinetics and molecular dynamics simulations to determine the effects of Zn2+ on acetaldehyde dehydrogenase 1

Paper ID Volume ID Publish Year Pages File Format Full-Text
34288 45016 2015 7 PDF Available
Title
Integration of inhibition kinetics and molecular dynamics simulations to determine the effects of Zn2+ on acetaldehyde dehydrogenase 1
Abstract

•The inhibitory effect of Zn2+ on acetaldehyde dehydrogenase 1 (ALDH1).•Integrating study between kinetics and computational molecular dynamics simulations.•Zn2+ ligand binding mechanisms to ALDH1.•Zn2+ potent application for ALDH1-associated human diseases.

Understanding the mechanism of inhibition of acetaldehyde dehydrogenase 1 (ALDH1) is clinically important because this enzyme is involved in several types of cancers and other diseases. In this study, we investigated the effects of Zn2+ on the structure of ALDH1 by integrating kinetic inhibition studies with computational simulations. Tertiary structure and hydrophobic surface changes were also assessed by measuring intrinsic and ANS-binding fluorescence. The crystallographic structure of ALDH1 was applied in computational docking as well as molecular dynamics simulations. We found that the direct binding of Zn2+ to ALDH1 induces structural changes and inhibits ALDH1 activity. Moreover, Zn2+-mediated inactivation of ALDH1 was associated with structural changes. Specifically, beta regions of ALDH1 were exposed upon binding of Zn2+ and underwent significant conformational changes, including the loss of beta secondary structure. Our study provides insight into the structural changes that accompany Zn2+-mediated inhibition of ALDH1. Our findings also suggest that Zn2+, a potent inhibitor of ALDH1, may be useful in the treatment of ALDH1-related diseases.

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Keywords
Acetaldehyde dehydrogenase 1; Zn2+; Inhibition kinetics; Molecular dynamicsALDH1, acetaldehyde dehydrogenase 1; ANS, 1-anilinonaphthalene-8-sulfonate; MD, molecular dynamics
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Publisher
Database: Elsevier - ScienceDirect
Journal: Process Biochemistry - Volume 50, Issue 11, November 2015, Pages 1878–1884
Authors
, , , , , , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us