Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Khanna, May; Chen, Che Hong; Kimble-Hill, Ann C.; Parajuli, Bibek; Perez‐Miller, Samantha; Baskaran, Sulochanadevi; Kim, Jeewon; Dria, Karl J.; Vasiliou, Vasilis; Mochly‐Rosen, Daria; Hurley, Thomas D.

doi:10.1074/jbc.m111.293597

Cited by 73 publications

(108 citation statements)

References 32 publications

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“…S1 A and B). Because the catalytic cavity of ALDH3A1 is bigger than that of ALDH2 (26), small aldehydes, such as acetaldehyde, are poorly metabolized by this enzyme (27). We reasoned that an Alda that binds to the ALDH3A1 catalytic cavity and reduces its size should improve the catalysis of small aldehydes, such as acetaldehyde, by ALDH3A1.…”

Section: Resultsmentioning

confidence: 99%

“…1 F and G). In ALDH2, the catalytic cavity consists mostly of aromatic amino acids (25), whereas ALDH3A1 contains more aliphatic and polar amino acids (26,29). In ALDH2, amino acids 455-460 form a loose chain, whereas the corresponding amino acids (389-396) in ALDH3A1 form an α-helix ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structures of ALDH2 and ALDH3A1 were obtained from the RCSB Protein Data Bank (PDB ID codes 3INL (25) and 3SZA (26). Waters and ligands were removed from the structure.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

Chen

Cruz

Mochly‐Rosen

2015

Proc. Natl. Acad. Sci. U.S.A.

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Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

Chen

Cruz

Mochly‐Rosen

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In mouse tracheal sections, we found expression of ALDH2 and ALDH3A1 in ABSCs and SMG duct cells and expression of ALDH1A1 in non-ABSCs. Of note, none of the chemical or small molecule agonists [30,31] and antagonists [25,26,32] that we used to specifically perturb ALDH1A1, ALDH2, or ALDH3A1 isozyme levels were completely specific for these isoforms, suggesting overlapping roles. In addition, it is possible that the agonists and antagonists that we used to target specific ALDH isoforms may have exerted their effect on specific ALDH isozymes early on in the time course of the in vitro cultures and other ALDH isozymes may have been upregulated or downregulated to compensate for the lack of ALDH activity.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase Activity Enriches for Proximal Airway Basal Stem Cells and Promotes Their Proliferation

Hegab

Ha²,

Bisht³

et al. 2014

Stem Cells and Development

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Both basal and submucosal gland (SMG) duct stem cells of the airway epithelium are capable of sphere formation in the in vitro sphere assay, although the efficiency at which this occurs is very low. We sought to improve this efficiency of sphere formation by identifying subpopulations of airway basal stem cells (ABSC) and SMG duct cells based on their aldehyde dehydrogenase (ALDH) activity. ALDH hi ABSCs and SMG duct cells were highly enriched for the population of cells that could make spheres, while the co-culture of ALDH hi differentiated cells with the ALDH hi ABSCs increased their sphere-forming efficiency. Specific ALDH agonists and antagonists were used to show that airway specific ALDH isozymes are important for ABSC proliferation. Pathway analysis of gene expression profiling of ALDH hi and ALDH lo ABSCs revealed a significant upregulation of the arachidonic acid (AA) metabolism pathway in ALDH hi ABSCs. We confirmed the importance of this pathway in the metabolism of proliferating ALDH hi ABSCs using bioenergetics studies as well as agonists and antagonists of the AA pathway. These studies could lead to the development of novel strategies for altering ABSC proliferation in the airway epithelium.

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“…Small molecules have potential advantages over other approaches, such as reversibility of action and rapid temporal inhibition. Previous smallmolecule screens have identified useful research tool compounds in the study of kinases [20][21][22] and aldehyde dehydrogenases 23 and have been successfully used to study the cellular functions of their targets. Compounds identified in this study and their derivatives could therefore serve as useful reagents for future investigations into the cellular role and regulation of RNase H2.…”

Section: The Group D Compound Structure Is a Potent Inhibitor Of Ribomentioning

confidence: 99%

Identification of Small-Molecule Inhibitors of the Ribonuclease H2 Enzyme

et al. 2013

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Ribonuclease H2 (RNase H2) is a nuclease that specifically hydrolyzes RNA residues in RNA-DNA hybrids. Mutations in the RNase H2 enzyme complex have been identified in the genetic disorder Aicardi-Goutières syndrome (AGS), which has similarities to the autoimmune disease systemic lupus eryrthrematosis (SLE). The RNase H2 enzyme has also been recently implicated as a key genome surveillance enzyme. Therefore, small-molecule modulators of RNase H2 activity may have utility in therapeutics and as tools to investigate the cellular functions of RNase H2. A fluorescent quench assay, measuring cleavage of an RNA-DNA duplex substrate by recombinant RNase H2, was developed into a high-throughput format and used to screen a 48 560 compound library. A hit validation strategy was subsequently employed, leading to the identification of two novel inhibitor compounds with in vitro nanomolar range inhibition of RNase H2 activity and >100-fold selectivity compared with RNase H type 1. These compounds are the first small-molecule inhibitors of RNase H2 to be reported. They and their derivatives should provide the basis for the development of tool compounds investigating the cellular functions of the RNase H2 enzyme, and, potentially, for pharmacological manipulation of nucleic acid-mediated immune responses.

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Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Cited by 73 publications

References 32 publications

Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

Aldehyde Dehydrogenase Activity Enriches for Proximal Airway Basal Stem Cells and Promotes Their Proliferation

Identification of Small-Molecule Inhibitors of the Ribonuclease H2 Enzyme

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