Aldehyde dehydrogenase (ALDH)

Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart. There are three different classes of these enzymes in mammals: class 1 (low Km, cytosolic), class 2 (low Km, mitochondrial), and class 3 (high Km, such as those expressed in tumors, stomach, and cornea). In all three classes, constitutive and inducible forms exist. ALDH1 and ALDH2 are the most important enzymes for aldehyde oxidation, and both are tetrameric enzymes composed of 54kDA subunits. These enzymes are found in many tissues of the body but are at the highest concentration in the liver.

NCT 501 hydrochloride
DEAB
120-21-8
142867-52-5
WIN 18446
1477-57-2
1780260-20-9
349438-38-6
Alda 1
349438-38-6
A37
896795-60-1

Background


Aldehyde dehydrogenase (ALDH) represent a group of evolutionarily-related, nicotinamide adenine dinucleotide-dependent enzymes that efficiently oxidize a wide variety of endogenous and exogenous aliphatic and aromatic aldehydes to their corresponding carboxylic acids. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions.

Members of this gene superfamily have significant physiologic roles as exemplified by the various clinical pathologies arising from genetic polymorphisms influencing a particular ALDH's normal function. ALDH1A1 is a ubiquitously expressed, cytosolic homo-tetramer (55 kDa) capable of oxidizing a wide spectrum of substrates including acetaldehyde, retinal, and 3-deoxyglucosone. Meanwhile, the ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. Over-expression of ALDH1A1 has been suggested to confer drug resistance to oxazaphosphorines, including cyclophosphamide, by metabolism of the aldophosphamide metabolite, thereby preventing the formation of the active metabolites acrolein and phosphoramide mustard. ALDH1A1's reported low K/ for 4-hydroxy-2-nonenal (4-HNE) suggests an important role in this aldehyde's metabolism particularly in areas where this enzyme is highly expressed as found in the cornea and lens tissues. ALDH3A1 is a dioxin inducible, cytosolic homo-dimer (50 kDa) involved in the oxidation of a variety of medium- and long-chain aliphatic and aromatic aldehydes. It is constitutively expressed at very high levels in the mammalian cornea, specifically, the epithelium and stromal matrix keratocytes and may play a significant role as an enzymatic antioxidant via its metabolism of 4-HNE. 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. ALDH3A1 and ALDH1A1 are two enzymes present in the corneal tissues that efficiently metabolize 4-HNE. These cytosolic proteins are NAD(P)+- and NAD+-dependent enzymes, respectively, that catalyze the oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding carboxylic acids. ALDH3A1 has been identified by immunofluorescence in both the epithelial and stromal matrix layers of the normal human cornea, but not in the endothelial layer. It was originally identified as a highly expressed protein in the bovine cornea and has subsequently been shown to constitute 10 to 40% of the total water-soluble protein in the corneas of mammalian species. ALDH1A1 is also ubiquitously expressed in mammalian corneal tissues, albeit to a much lesser degree than ALDH3A1. Interestingly, the cornea of rabbits completely lacks the ALDH3A1 expressed in the cornea of other mammals and appears to compensate for this deficit with elevated levels of ALDH1A1.

ALDHs have the capacity to influence neural function, particularly in dopaminergic nerves. Both ALDH1A1 and ALDH2 have been implicated in dopamine metabolism. Inhibition of these isozymes leads to the accumulation of neurotoxic dopamine metabolites, such as 3,4-dihydroxyphenylacetaldehyde, that are thought to contribute to the pathogenesis of Parkinson's disease. Dopaminergic pathways are involved in the reinforcing effects of cocaine addiction. Inhibition of ALDH2 suppresses cocaine-seeking behavior in conditioned rats through a 3,4-dihydroxyphenylacetaldehyde-dependent decrease in dopamine synthesis. Likewise, ethanol consumption by rodents has been shown to be reduced by ALDH inhibitor treatment through a mechanism independent of increases in systemic levels of acetaldehyde and potentially involving suppression of central dopamine release. Such a central nervous system mechanism may contribute to the low incidence of alcohol consumption/addiction observed in subjects harboring the ALDH2*2 genetic variant that encodes the inactive ALDH2 enzyme. In addition, the isozyme ALDH5A1, also known as mitochondrial succinic semialdehyde dehydrogenase, is an important regulator of GABA metabolism. It is believed that, through their metabolic functions, ALDHs have a significant involvement in neuroprotection.

Reference:WILLIAM JOHN BLACK. THE PROTECTIVE ROLE OF ALDEHYDE DEHYDROGENASE ALDH3A1 AGAINST 4-HYDROXY-2-NONENAL IN THE CORNEAL STROMAL MATRIX KERATOCYTES