A computational integrating kinetic study on the flexible active site of human acetaldehyde dehydrogenase 1. Issue 6 (June 2016)

• Record Type: Journal Article
• Authors: Xu, Yingying; Lee, Jinhyuk; Yang, Hee Seung; Lü, Zhi-Rong; Mu, Hang; Yang, Jun-Mo; Zhang, Qian; Park, Yong-Doo
• Is Part Of: Process biochemistry. Volume 51:Issue 6(2016:Jun.)
• Page Start: 725
• Page End: 733
• Publication Date: 2016-06
• Subjects: ALDH1 acetaldehyde dehydrogenase 1 -- GdnHCl guanidine hydrochloride -- ANS 1-anilinonaphthalene-8-sulfonate -- MD molecular dynamics; ALDH1 -- Guanidine hydrochloride -- Kinetics -- MD simulation -- Active site; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2016.03.009
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: The guanidine mediated inactivation of acetaldehyde dehydrogenase 1 (ALDH1). Active site conformational modulation of ALDH1 by guanidine binding. Integrating study between kinetics and computational molecular dynamics simulations. Flexible active site pocket of ALDH1. Abstract: In order to gain more insight into the relation between the structure of acetaldehyde dehydrogenase 1 (ALDH1) and its catalytic and regional active site properties, the denaturant guanidine hydrochloride (GdnHCl) was employed in this study. The effects of GdnHCl on ALDH1 conformational and functional changes were evaluated by kinetic analysis and by performing computational molecular dynamics (MD) simulations. We found that direct binding of GdnHCl to ALDH1 induced complete inactivation prior to conspicuous changes in its tertiary structure or hydrophobic exposure, indicating that the active site is flexible compared to the overall structure. Kinetic experimental results and computational simulations indicated that there are specific sites on ALDH1 to which guanidine binds, resulting in blocking of catalytic function without a large degree of structural disruption. These sites may lay specifically in a cofactor-binding region, which was suggested by the observation of mixed-type inhibition. Our study provides insight into the flexibility of the ALDH1 active site through the use of GdnHCl denaturant and computational simulations to suggest possible binding mechanisms of inhibitors for the clinical applications.