Human ocular aldehyde dehydrogenase isozymes: Distribution and properties as major soluble proteins in cornea and lens

King, Gordon; Holmes, Roger S.

doi:10.1002/(sici)1097-010x(199809/10)282:1/2<12::aid-jez4>3.0.co;2-q

Cited by 44 publications

(6 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression pattern of ALDHs between humans and rabbits is also consistent with a closer evolutionary link of humans with rabbits than rodents. Humans express much less corneal ALDH3A1 (5% rather than ϳ50% of the water-soluble protein) but more corneal ALDH1A1 (3%) than do mice (trace amounts at best) (31). The fact that rabbit ALDH1A1 comprises 16.1% of the total water-soluble protein of the corneal stroma is also consistent with our present finding of greater activity of the rabbit Aldh1a1 promoter than of the human Aldh1a1 promoter in the transfected corneal stromal cells.…”

Section: Discussionsupporting

confidence: 88%

See 1 more Smart Citation

Preferential Transcription of Rabbit Aldh1a1 in the Cornea: Implication of Hypoxia-Related Pathways

Hough

Piatigorsky

2004

Molecular and Cellular Biology

View full text Add to dashboard Cite

Here we examine the molecular basis for the known preferential expression of rabbit aldehyde dehydrogenase class 1 (ALDH1A1) in the cornea. The rabbit Aldh1a1 promoter-firefly luciferase reporter transgene (؊3519 to ؉43) was expressed preferentially in corneal cells in transfection tests and in transgenic mice, with an expression pattern resembling that of rabbit Aldh1a1. The 5 flanking region of the rabbit Aldh1a1 gene resembled that in the human gene (60.2%) more closely than that in the mouse (46%) or rat (51.5%) genes. We detected three xenobiotic response elements (XREs) and one E-box consensus sequence in the rabbit Aldh1a1 upstream region; these elements are prevalent in other highly expressed corneal genes and can mediate stimulation by dioxin and repression by CoCl 2 , which simulates hypoxia. The rabbit Aldh1a1 promoter was stimulated fourfold by dioxin in human hepatoma cells and repressed threefold by CoCl 2 treatment in rabbit corneal stromal and epithelial cells. Cotransfection, mutagenesis, and gel retardation experiments implicated the hypoxia-inducible factor 3␣/aryl hydrocarbon nuclear translocator heterodimer for Aldh1a1 promoter activation via the XREs and stimulated by retinoic acid protein 13 for promoter repression via the E-box. These experiments suggest that XREs, E-boxes, and PAS domain/basic helix-loop-helix transcription factors (bHLH-PAS) contribute to preferential rabbit Aldh1a1 promoter activity in the cornea, implicating hypoxia-related pathways.Most mammalian corneas accumulate (5 to 40% depending on species) aldehyde dehydrogenase 3 (ALDH3A1) (unified nomenclature for the ALDH gene family [http://www.uchsc .edu/sp/sp/alcdbase/alcdbase.html]) mostly, but not exclusively, in their epithelium (47). While the function of the abundant ALDH3A1 in mammalian corneal epithelial cells is not established, detoxification of lipid peroxide radicals induced by UV light (26), absorption of UV (1), and a suspected structural role (47) are among the suggested possibilities. The fact that elimination of mouse ALDH3A1 (50% of corneal water-soluble protein) by homologous recombination in mice fails to show a corneal phenotype has increased the mystery of its function (44). Deficiencies in ALDH have also been implicated in keratoconus, which affects the corneal epithelium (18).Rabbits are exceptional in that they accumulate ALDH1A1 rather than ALDH3A1 in the cornea (29). ALDH1A1 comprises about 3% and ALDH3A1 comprises about 5% of the total soluble protein in human cornea (31). In contrast to the situation with ALDH3A1 in other mammals, rabbit ALDH1A1 is more abundant in the stromal cells of the cornea than in the epithelium. Wound healing experiments after freeze-induced injury suggested that the prevalence of ALDH1A1 may contribute to transparency of rabbit stromal cells (29), analogous to the role of crystallins in the lens. Indeed, -crystallin (ALDH1A8) is a lens crystallin, comprising 25% of the watersoluble protein of the elephant shrew lens (20). A protein equally similar to ALDH1A1 and ALDH2...

show abstract

Section: Discussionsupporting

confidence: 88%

“…ALDH1A1 comprises about 3% and ALDH3A1 comprises about 5% of the total soluble protein in human cornea (31). In contrast to the situation with ALDH3A1 in other mammals, rabbit ALDH1A1 is more abundant in the stromal cells of the cornea than in the epithelium.…”

supporting

confidence: 90%

Preferential Transcription of Rabbit Aldh1a1 in the Cornea: Implication of Hypoxia-Related Pathways

Hough

Piatigorsky

2004

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…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: 84%

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.

View full text Add to dashboard Cite

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.

show abstract

“…Previous studies by Choudhary et al (2003) and King et al (1998) showed that ALDH1A1 is the predominant ALDH isozyme in rat lenses and human lens epithelial cells (HLEC). In this study, ALDH1A1 was successfully amplified and cloned from human lens cDNA library.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Oxidative Modification of Human Lens ALDH1A1: Implication in Impaired Detoxification of Lipid Aldehydes

Xiao

Shoeb

Siddiqui

et al. 2009

Journal of Toxicology and Environmental Health, Part A

View full text Add to dashboard Cite

Earlier studies showed that human lens ALDH1A1 plays a critical role in protection against oxidative stress-induced cytotoxicity in human lens epithelial cells (HLEC), and opacification of rat and mouse lens. The complete coding sequence of ALDH1A1 was cloned from human lens cDNA library by using PCR methods and expressed it in Escherichia coli. The cloned human lens ALDH1A1 cDNA encodes a 501-amino-acid protein (molecular mass = 54.8 kD) that is 100% identical to human liver ALDH1A1 and shares significant identity with the same isozyme from other tissues and species. The purified recombinant human lens ALDH1A1 exhibited optimal catalytic activity at pH 8 and preferred NAD+ as cofactor and specifically catalyzed the oxidation of toxic lipid aldehydes such as 4-hydroxynonenal (HNE; Km = 4.8 µM) and malonaldehyde (Km MDA = 3.5 µM). Citral, disulfiram, and cyanamide were found to inhibit human lens ALDH1A1 at IC50 values of 55, 101, and 22610 µM, respectively, whereas diethylstilbestrol (DES) was found to be an activator (EC50, 1.3 µM). Further, modification of recombinant human lens ALDH1A1 with nitric oxide donors such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) significantly inhibited the enzyme activity. It therefore appears that activation of ALDH1A1, which efficiently catalyzes the detoxification of lipid-derived toxic aldehydes, and/or prevention of its oxidative modification may be novel therapeutic interventions against oxidative stress-induced lens pathologies.

show abstract

Human ocular aldehyde dehydrogenase isozymes: Distribution and properties as major soluble proteins in cornea and lens

Cited by 44 publications

References 20 publications

Preferential Transcription of Rabbit Aldh1a1 in the Cornea: Implication of Hypoxia-Related Pathways

Preferential Transcription of Rabbit Aldh1a1 in the Cornea: Implication of Hypoxia-Related Pathways

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

Molecular Cloning and Oxidative Modification of Human Lens ALDH1A1: Implication in Impaired Detoxification of Lipid Aldehydes

Contact Info

Product

Resources

About