Human Aldehyde Dehydrogenase Catalytic Activity and Structural Interactions with Coenzyme Analogs

Izaguirre, Gonzalo; Pietruszko, Regina; Cho, Samuel K.; MacKerell, Alexander D.

doi:10.1080/07391102.2001.10506752

Cited by 5 publications

(3 citation statements)

References 61 publications

(51 reference statements)

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“…A previous study indicated that ALDH1 had the broadest substrate specificity among isozymes of the ALDH enzyme family, and some residues of the active site were closely related with coenzyme binding, hydrophobicity, and structural perturbation [25]. Other mammalian-originated crystal structures of ALDH1 revealed that elephant ALDH1 has a Fig.…”

Section: Discussionmentioning

confidence: 97%

Integration of Inhibition Kinetics and Molecular Dynamics Simulations: A Urea-Mediated Folding Study on Acetaldehyde Dehydrogenase 1

Lee

et al. 2016

Appl Biochem Biotechnol

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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.

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Section: Discussionmentioning

confidence: 97%

Integration of Inhibition Kinetics and Molecular Dynamics Simulations: A Urea-Mediated Folding Study on Acetaldehyde Dehydrogenase 1

Lee

et al. 2016

Appl Biochem Biotechnol

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“…Within the ALDH family, research interest has been drawn to protein-ligand binding affinities and catalytic mechanisms 16 , 22 , 23 , 26 , 27 . The highly conserved sequence in the catalytic pocket defines similar residues for catalysis.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into betaine aldehyde dehydrogenase (BADH2) from Oryza sativa explored by modeling and simulations

Baicharoen

Vijayan

Pongprayoon

2018

Sci Rep

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Betaine aldehyde dehydrogenase 2 (BADH2) plays a key role in the accumulation of 2-acetyl-1-pyrroline (2AP), a fragrant compound in rice (Oryza sativa). BADH2 catalyses the oxidation of aminoaldehydes to carboxylic acids. An inactive BADH2 is known to promote fragrance in rice. The 3D structure and atomic level protein-ligand interactions are currently unknown. Here, the 3D dimeric structure of BADH2 was modeled using homology modeling. Furthermore, two 0.5 µs simulations were performed to explore the nature of BADH2 dimer structurally and dynamically. Each monomer comprises of 3 domains (substrate-binding, NAD+-binding, and oligomerization domains). The NAD+-binding domain is the most mobile. A scissor-like motion was observed between the monomers. Inside the binding pocket, N162 and E260 are tethered by strong hydrogen bonds to residues in close proximity. In contrast, the catalytic C294 is very mobile and interacts occasionally with N162. The flexibility of the nucleophilic C294 could facilitate the attack of free carbonyl on an aldehyde substrate. Key inter-subunit salt bridges contributing to dimerization were also identified. E487, D491, E492, K498, and K502 were found to form strong salt bridges with charged residues on the adjacent monomer. Specifically, the nearly permanent R430-E487 hydrogen bond (>90%) highlights its key role in dimer association. Structural and dynamic insights of BADH2 obtained here could play a role in the improvement of rice fragrance, which could lead to an enhancement in rice quality and market price.

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“…Eventually, the thioester is hydrolysed by a water molecule to carboxylic acid. The sequential dissociation of carboxylic acid and NADH, which is the rate-limiting step, ends the reaction [14] , [16] .…”

Section: Introductionmentioning

confidence: 99%

Interaction of Aldehyde dehydrogenase with acetaminophen as examined by spectroscopies and molecular docking

Kolawole

2017

Biochemistry and Biophysics Reports

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The interaction of acetaminophen, a non-substrate anionic ligand, with Aldehyde Dehydrogenase was studied by fluorescence, UV–Vis absorption, and circular dichroism spectroscopies under simulated physiological conditions. The fluorescence spectra and data generated showed that acetaminophen binding to ALDH is purely dynamic quenching mechanism. The acetaminophen-ALDH is kinetically rapid reversible interaction with a binding constant, Ka, of 4.91×103 L mol−1. There was an existence of second binding site of ALDH for acetaminophen at saturating acetaminophen concentration. The binding sites were non-cooperative. The thermodynamic parameters obtained suggest that Van der Waal force and hydrogen bonding played a major role in the binding of acetaminophen to ALDH. The interaction caused perturbation of the ALDH structures with an obvious reduction in the α-helix. The binding distance of 4.43 nm was obtained between Acetaminophen and ALDH. Using Ficoll 400 as macro-viscosogen and glycerol as micro-viscosogen, Stoke-Einstein empirical plot demonstrated that acetaminophen-ALDH binding was diffusion controlled. Molecular docking showed the participation of some amino acids in the complex formation with −5.3 kcal binding energy. With these, ALDH might not an excipient detoxifier of acetaminophen but could be involved in its pegylation/encapsulation.

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Human Aldehyde Dehydrogenase Catalytic Activity and Structural Interactions with Coenzyme Analogs

Cited by 5 publications

References 61 publications

Integration of Inhibition Kinetics and Molecular Dynamics Simulations: A Urea-Mediated Folding Study on Acetaldehyde Dehydrogenase 1

Integration of Inhibition Kinetics and Molecular Dynamics Simulations: A Urea-Mediated Folding Study on Acetaldehyde Dehydrogenase 1

Structural insights into betaine aldehyde dehydrogenase (BADH2) from Oryza sativa explored by modeling and simulations

Interaction of Aldehyde dehydrogenase with acetaminophen as examined by spectroscopies and molecular docking

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