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Review
. 2012 Jul;64(3):520-39.
doi: 10.1124/pr.111.005538. Epub 2012 Apr 27.

Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application

Vindhya Koppaka  1 , David C Thompson, Ying Chen, Manuel Ellermann, Kyriacos C Nicolaou, Risto O Juvonen, Dennis Petersen, Richard A Deitrich, Thomas D Hurley, Vasilis Vasiliou
Affiliations
Review

Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application

"V体育官网入口" Vindhya Koppaka et al. Pharmacol Rev. 2012 Jul.

"V体育官网入口" Abstract

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis VSports手机版. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents. .

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Figures

Fig. 1.
Fig. 1.
The ALDH superfamily of enzymes. Clustering dendrogram depicting the evolution of mammalian ALDHs from a single gene, their human chromosomal location, preferred substrate, and available X-ray crystal structures from the Research Collaboratory for Structural Bioinformatics (RCSB-PDB) database. *, substrate for hydrolase reaction of ALDH1L2 (Strickland et al., 2011). [Modified from Marchitti SA, Deitrich RA, and Vasiliou V (2007) Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 59:125–150. Copyright © 2007 American Society for Pharmacology and Experimental Therapeutics. Used with permission.]
Fig. 2.
Fig. 2.
Molecular architecture of ALDH isozymes. A, the representative ALDH monomer visualized from Protein Data Bank code 1O01 (Perez-Miller and Hurley, 2003): human mitochondrial aldehyde dehydrogenase complexed with crotonaldehyde, NADH, and Mg2+. The functional regions are highlighted: catalytic domain (brown), NAD binding domain (purple), and oligomerization domain (green). B, top view of the monomer showing active site area. C, magnified view of B showing Cys302 (a), aldehyde substrate (b), ordered water molecule between Glu268 and Cys302 (c), Glu268 (d), Mg2+ ion (e; not drawn to scale), and NADH cofactor (f).
Fig. 3.
Fig. 3.
A, mechanism of aldehyde oxidation. 1, activation of the catalytic Cys302 by the ordered water molecule and Glu268 through proton abstraction. 2, nucleophilic attack on the carbonyl carbon of the aldehyde by the thiolate group of the catalytic Cys302. 3, formation of the tetrahedral thiohemiacetal intermediate (deacylation) and hydride transfer from the tetrahedral thiohemiacetal intermediate to the pyridine ring of NAD+. 4, hydrolysis of the resulting thioester intermediate. 5, dissociation of the reduced cofactor and subsequent regeneration of the enzyme by NAD+ binding. B, proposed mechanism of ester hydrolysis. 1, catalytic cysteine residue is activated by hydrogen abstraction from a basic residue (Glu268) in catalytic site. 2, thiolate ion attacks the substrate p-nitrophenyl acetate leading to oxyanion intermediate formation. 3, the intermediate rearranges and nitrophenolic group leaves. 4, Glu268 residue abstracts hydrogen from nearby ordered water molecule, making it a nucleophile. It attacks the carbonyl in the thioacyl enzyme complex. 5, formation of the tetrahedral intermediate that again rearranges to release acetic acid and free enzyme.
Fig. 4.
Fig. 4.
Active site topography. The active site is located at the base of a hydrophobic tunnel located 12 Å from the surface of the enzyme. a, lipophilic surface potential rendering of the ALDH2 structure (1O01) (Perez-Miller and Hurley, 2003). The lipophilic potential is indicated by a color code (blue, hydrophilic; green/brown, hydrophobic). b, inset magnification of tunnel from a with the substrate in view. c, side view of the enzyme in a, with enzyme structure in blue ribbon and lipophilic surface in green and brown; the hydrophobic tunnel is shown in brackets with NADH, aldehyde substrate (ball and stick models), and magnesium ion (purple sphere) inside.
Fig. 5.
Fig. 5.
Benomyl and its active metabolites. Benomyl is metabolized to BIC. BIC is then conjugated with GSH to form GSBT. Under the action of γ-glutamyltranspeptidase, GSBT is transformed to Cys-BT. β-Lyase then converts Cys-BT to N-butylthiocarbamic acid, which is then converted to MBT. Under the action of P450s, MBT gives rise to various sulfoxide and N-hydroxyl products that inhibit the ALDH2 active site through carbomylation of the active cysteine. [Adapted from Staub RE, Quistad GB, and Casida JE (1998) Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice. Chem Res Toxicol 11:535–543. Copyright © 1998 American Chemical Society. Used with permission.]
Fig. 6.
Fig. 6.
Structural analogs of chlorpropamide. Ester analog of chlorpropamide, (benzoyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-1). Alkyl analog of chlorpropamide, 4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamide (API-1). [Reprinted from Rekha GK, Devaraj VR, Sreerama L, Lee MJ, Nagasawa HT, and Sladek NE (1998) Inhibition of human class 3 aldehyde dehydrogenase, and sensitization of tumor cells that express significant amounts of this enzyme to oxazaphosphorines, by chlorpropamide analogues. Biochem Pharmacol 55:465–474. Copyright © 1998 Elsevier. Used with permission.]
Fig. 7.
Fig. 7.
Cyanamide inhibition of ALDH. Bioactivation of cyanamide releases nitroxyl as the active inhibitor, which inhibits irreversibly through sulfonamide formation (1) or reversibly through intersubunit disulfide formation (2).
Fig. 8.
Fig. 8.
Antioxidant isoflavones. Inhibition of ALDH2 by daidzin and CVT-10216 is dependent on a conserved isoflavone moiety (box) and a 4′-substituent identified as the essential pharmacophore.
Fig. 9.
Fig. 9.
Disulfiram and its metabolites. DDTC is liberated from disulfiram by disulfide exchange with the catalytic cysteine of ALDH. Hepatic thiomethyl transferases subsequently give rise to all of the other metabolites. [Adapted from Pike MG, Mays DC, Macomber DW, and Lipsky JJ (2001) Metabolism of a disulfiram metabolite, S-methylN,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes. Drug Metab Dispos 29:127–132. Copyright © 2001 American Society for Pharmacology and Experimental Therapeutics. Used with permission.]
Fig. 10.
Fig. 10.
Molinate and its active metabolites. Molinate is metabolized to molinate sulfoxide and finally to molinate sulfone. [Reprinted from Allen EM, Anderson DG, Florang VR, Khanna M, Hurley TD, and Doorn JA (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition. Chem Res Toxicol 23:1843–1850. Copyright © 2010 American Chemical Society. Used with permission.]
Fig. 11.
Fig. 11.
Nitroglycerin interactions with ALDH. GTN is hydrolyzed by ALDH to form 1,2-glyceryl dinitrate (1,2 GDN) and a thionitrate intermediate bound to the ALDH active site cysteine (Cys302). Two proposed pathways can then be followed: in pathway A, an adjacent cysteine in the active site (Cys301) attacks the thiol of Cys302, forming a disulfide bond and releasing nitrite ion. The nitrite ion gets further metabolized to release NO, which induces vasodilation, whereas the ALDH enzyme is oxidized. In pathway B, the thionitrate intermediate rearranges to form sulfenyl nitrite, which leads to the formation of either a sulfinyl radical (C) and NO or an inactivated sulfinate (D) and HNO. [Adapted from Wenzl MV, Beretta M, Griesberger M, Russwurm M, Koesling D, Schmidt K, Mayer B, and Gorren AC (2011) Site-directed mutagenesis of aldehyde dehydrogenase-2 suggests three distinct pathways of nitroglycerin biotransformation. Mol Pharmacol 80:258–266. Copyright © 2011 American Society for Pharmacology and Experimental Therapeutics. Used with permission.]
Fig. 12.
Fig. 12.
Pargyline metabolism. CYP 2E1-mediated activation of pargyline via N-depropargylation (A), N-demethylation (B), N-debenzylation (C), and N-oxidation (D). N-methylpropargylamine and N-benzylpropargylamine are metabolized further by P450s (E) to yield propioaldehyde as the final effector of ALDH inactivation. Major and minor pathways are depicted by solid and dashed lines, respectively. [Adapted from DeMaster EG, Shirota FN, and Nagasawa HT (1986) Role of propiolaldehyde and other metabolites in the pargyline inhibition of rat liver aldehyde dehydrogenase. Biochem Pharmacol 35:1481–1489. Copyright © 1986 Elsevier. Used with permission.]
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