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ALDH Genes


ALDH 1 Family
ALDH 2 Family
ALDH 3 Family
ALDH 4 Family
ALDH 5 Family
ALDH 6 Family
ALDH 7 Family
ALDH 8 Family
ALDH 9 Family
ALDH 10 Family
ALDH 11 Family
ALDH 12 Family
ALDH 16 Family
ALDH 18 Family
ALDH 22 Family

ALDH 1 Family

ALDH1A1
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Summary:

The ALDH1A1 gene product is a cytosolic homo-tetramer (~55 kDa subunits) expressed in a number of tissues including brain, cornea, lens, retina, liver, and gastrointestinal tract (9723161) (11744377) (9973596) . ALDH1A1 is one of four known vertebrate retinaldehyde dehydrogenases and is often referred to in the literature as RALDH1 (1292933) retaining a high affinity for all-trans and 9-cis-retinaldehyde (Km < 0.1 umol/L) and acetaldehyde (Km ~ 50-100 umol/L) (1292933) .

The retinaldehyde dehydrogenases play a significant role in vertebrate embryogenesis. Retinoic acid (RA) is a low molecular weight (300 Da), lipophilic, rapidly-diffusing signaling molecule essential for growth and developmental processes in the embryo. It is produced in vivo via a two-step enzymatic pathway oxidizing retinols such as vitamin A (all-trans-retinol) by specific cytosolic alcohol or microsomal retinol dehydrogenases to retinaldehyde and then to retinoic acid by one of several cytosolic retinaldehyde dehydrogenases. ALDH1A1 was first shown to catalyze the irreversible oxidation of retinaldehyde to its carboxylic acid, retinoic acid (10880953) . Studies have been conducted to address the role of ALDH1A1 genes during organogenesis and embryonic development using transgenic and knockout animals (11744377) . These studies have shown that the pups are viable and may demonstrate redundancies in retinoic acid synthesis during development.

ALDH1A1\'s abundant expression in the mammalian cornea and lens categorizes it as a corneal crystalline based on the similarity in the level of expression to lens enzyme crystallins (9695791) (9599288) . Although the exact function of this enzyme in the cornea and lens remains a matter of controversy there is evidence that it may play a role in the development and/or maintenance of tissue transparency through its affects on light-scattering and absorption (9973596) as well as a metabolic role in mitigating the effects of oxidative stress (12941160) .

ALDH1A1 has been linked to drug resistance against oxazaphosphorines, including cyclophosphamide in various tumor types (7484368) (8124665) . Its over-expression in a number of cell lines and normal hematopoietic progenitor cells results in a significant increase in resistance to the active metabolites of cyclophosphamide (10773007) .

ALDH1A1 has been implicated in several alcohol-related phenotypes including alcoholism, alcohol-induced flushing and alcohol sensitivity. Acetaldehyde formed during ethanol metabolism is efficiently metabolized by ALDH1A1 to non-toxic metabolites. Due to the role of ALDH1A1 in acetaldehyde metabolism, ALDH1A1 inhibition by the anti-alcoholic medication, disulfiram (>90%) or low ALDH1A1 activity due to polymorphisms contribute to alcohol sensitivity and alcohol-induced flushing.

 
 
ALDH1A2
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Summary:

ALDH1A2, a retinaldehyde dehydrogenase often referred to as RALDH2 is a cytosolic homotetramer (~56.7 kDa subunits) exhibiting complex expression patterns throughout embryonic development. This suggests that ALDH1A2 plays a role in retinoid metabolism during embryonic development where it is considered to be the major retinoic acid-synthesizing enzyme during early embryogenesis (10570467) . Study of three of the four retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2 and ALDH1A3) in knockout mice demonstrated ALDH1A2 induced lethal developmental defects owing to defective heart and forebrain development (11744377) (16368932) (14623956) .

ALDH1A2 is much less abundant and expressed in an organ- and tissue-specific manner in the adult mouse tissues, including liver. A recent study has demonstrated ALDH1A2 is expressed in normal prostate epithelia but is down-regulated in prostate cancer. Thus, ALDH1A2 may function as a tumor suppressor in prostate cancer and suggests a role of retinoids in the prevention or treatment of prostate cancer. ALDH1A2 may be a susceptible target for tumor suppression (16166285) .

Transgenic mice lacking Aldh1a2 die at mid-gestation without undergoing axial rotation, suggesting the importance of both Aldh1a2 and retinoic acid in embryonic development (10192400) .

 
 
ALDH1A3
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ALDH1A3 is a cytosolic homotetramer (~56 kDa subunits) and is expressed in an organ- and tissue specific manner at low levels in most organs but at higher levels in the salivary gland, stomach and kidney (7698756) . ALDH1A3 is often referred to as the third retinaldehyde dehydrogenase, RALDH3. Like ALDH1A2, it is differentially activated during early embryonic head and forebrain development. Studies using ALDH1A3 knockout mice demonstrated perinatal lethality due to nasal defects that occurred during embryonic development (14623956) .

 
 
ALDH1A7
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Aldh1a7 is considered a retinaldehyde dehydrogenase, however, it is only expressed in the mouse and rat.

 
 
ALDH1B1
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ALDH1B1 is an NAD+-dependent mitochondrial homotetramer (~57.3 kDa subunits) expressed in the liver and testis (2061311) as well as kidney, skeletal muscle and fetal tissues (7779080) . ALDH1B1 may also be expressed in the cornea although further investigation is required as only a partial sequence of the enzyme has been identified (8493893) . ALDH1B1 is unique from other ALDHs by virtue being encoded by an intron-less gene. This enzyme has ~72% sequence homology to ALDH2 and is insensitive to inhibition by disulfiram.

 
 
ALDH1L1
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ALDH1L1 is a large cytosolic protein (~98.8 kDa) highly expressed in the liver, representing up to 1% of the total pool of soluble cell protein in the mammalian liver cytosol (12065246) , (3196754) .

ALDH1L1 is responsible for catalyzing the NAD(P)+-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 (985432) and NAD(P)+-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate (4384443) .

Folates are essential for normal cell function and disruption of folate metabolism results in impaired cell division, altered protein expression, decreased DNA repair capability with accumulation of DNA damage, increased chromosomal aberrations and fragility, reduced growth rate and impairment of cell division (12065246) . Rapidly proliferating cancer cells in particular are susceptible to disruption of folate metabolism due to a significant requirement of folate pools for DNA/RNA synthesis necessary for rapid division.

ALDH1L1 is involved in two reactions of de novo purine biosynthesis, thus, several physiological functions have been suggested for this enzyme (16627483) including removal of excess pools of folate-activated one-carbon units (985432) , (8961940) , sequestration of cellular folate in the form of tetrahydrofolate (7840609) , and inhibition of purine synthesis and subsequent regulation of cell proliferation by depleting cellular 10-formyltetrahydrofolate pools required during two steps of this process (12065246) , (12805405) .

ALDH1L1 is required for purine biosynthesis thus its inhibition results in the depletion of intracellular 10-formyltetrahydrofolate followed by the loss of de novo purine biosynthesis. This diminishes DNA/RNA availability and ultimately induces an apoptotic cell death. Therefore downregulation of ALDH1L1 in tumors may serve to enhance proliferation (12065246) .

 
 
ALDH1L2
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ALDH1L2 has very similar homology to ALDH1L1 and is also a fusion gene, however, no functional data have yet been reported for this protein.

 
 

ALDH 2 Family

ALDH2
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Summary:

The ALDH2 gene product is a mitochondrial matrix homotetramer (~56.4 kDa subunits).

Based on the current nomenclature system, ALDH2 should be considered a member of the ALDH1B subfamily (>70% sequence homology) however, it was granted inclusion in the ALDH2 family due to the volume of literature regarding this enzyme as ALDH2.

ALDH2 has a broad expression pattern and is most notably involved in the second step of ethanol metabolism, the oxidation of acetaldehyde.

A large portion of individuals of Far East asian descent (~40%) have a functional polymorphism in the gene encoding ALDH2 (ALDH2*2) leading to a partially inactive form of the enzyme. This results in acetaldehyde accumulation and an alcohol-induced flushing reaction (10606490) , an increased level of response to alcohol and as a consequence, lower rates of alcoholism in this population (7625477) , (11925062) . In the mutant ALDH2 enzyme Glu487 has been replaced by a lysine and does not bind to AMP-sepharose chromatographic medium due to a decreased affinity for NAD+ (7910607) .

More recently, ALDH2 has been identified as a major enzyme responsible for bioactivation of nitroglycerin, used to treat angina and heart failure (17055381) .

 
 
ALDH2B4
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ALDH2B5
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ALDH2B7
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ALDH 3 Family

ALDH3A1
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Summary:

ALDH3A1 is a cytosolic homodimer (~50.4 kDa subunits) (4073832) constitutively expressed at considerably high levels (10-40% of the water-soluble protein) in the cornea of several mammalian species including humans (9723161) , (2802624) , (10376761) , (8617795) .

ALDH3A1 may have been recruited by gene sharing as major corneal proteins, called crystallins, which serve as structural elements in the eye (9599288) .

The specific roles of ALDH3A1 are a matter of current investigations and may include maintenance of corneal transparency, protection of lens crystallins by hydroxyl radical (•OH) scavenging (8670773) , direct absorption of UV-light (2209753) , generation of NAD(P)H for glutathione reduction and UVB absorption, and metabolism of cytotoxic aldehydes generated from UV-induced lipid peroxidation (12706498) , (12943535) , (8260946) .

Further investigations have implicated ALDH3A1 as a negative cell cycle regulator elongating the cell cycle and altering checkpoint protein expression levels (15905174) .

The protective role of ALDH3A1 in the cornea is apparent by studies in SWR/J mice that exhibit limited functionality of this enzyme (8500338) , (8131409) due to four amino acid substitutions (G88R, I154N, H305R and I352V) leading to complete loss of the ALDH3A1 catalytic activity (10376761) . These mice display significant sensitivities to UV-induced corneal clouding compared to wild type mice expressing ALDH3A1 (10376761) , (9192162) .

The rabbit is the only mammalian species examined thus far that lacks ALDH3A1 expression in the cornea. This lack of expression is believed to be compensated for by elevated levels of ALDH1A1 (12604188) .

ALDH3A1 and ALDH3A2 are primarily involved in the oxidation of medium- and long-chain aliphatic and aromatic aldehydes. Both of these genes are also dioxin-inducible.

 
 
ALDH3A2
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ALDH3A2 is a microsomal NAD+-dependent homodimer (~54.8 kDa subunits) necessary for the oxidation of long-chain aliphatic aldehydes to fatty acids (9133646) .

A heterogenous group of mutations in the ALDH3A2 gene have been identified as a causal link to Sjogren-Larsson Syndrome (SLS), an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of ALDH3A2 (11306053) , (10577908) .

 
 
ALDH3B1
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ALDH3B1 is a mitochondrial homodimer first cloned and sequenced by Hsu et al (7828891) .

ALDH3B1 is expressed in the kidney, lung and brain at elevated levels.

The structures of both ALDH3B1 and ALDH3B2 were reported in 1997 and suggest that from the conserved positions of the introns, gene duplication is involved in the expansion of the ALDH gene family (9161417) .

 
 
ALDH3B2
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ALDH3B2 is a mitochondrial homodimer. No functional data has been reported in the literature for ALDH3B2.

 
 
ALDH3F1
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ALDH3F2
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ALDH3H1
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ALDH3I1
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ALDH 4 Family

ALDH4A1
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ALDH4A1, a mitochondrial matrix homodimer (~61.7 kDa subunits), catalyzes the second step in the proline degradation pathway - the irreversible conversion of Δ1-pyrroline-5-carboxylate (P5C) derived either from proline or ornithine to glutamate. This reaction is a necessary step connecting the urea and tricarboxylic acid cycles.

Mutations in ALDH4A1 lead to type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of P5C and proline resulting in neurological manifestations including seizures and mental retardation (9700195) , (8621661) .

Recent studies have shown that ALDH4A1 is transcriptionally induced by p53 and potentially may have a protective role during cellular stress (14986171) .

The Rattus norvegicus homolog of ALDH4A1 does not appear to be characterized in NCBI, UniProt and Ensembl databases.

 
 

ALDH 5 Family

ALDH5A1
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ALDH5A1 encodes, a mitochondrial enzyme (~ 58.6 kDa subunits) often referred to as succinic semialdehyde dehydrogenase involved in the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) and is highly expressed in the brain.

Several mutations have been identified in both coding and non-coding segments of the ALDH5A1 leading to a functional deficiency in the gene product. This rare autosomal recessive metabolic disorder of 4-aminobutyric acid degradation is characterized by the accumulation of GABA and 4-hydroxybutryic acid leading to a variety of moderate to severe phenotypic neurological disorders including mental retardation, ataxia and seizures (9093300) .

ALDH5A1 knockout mice are characterized biochemically by elevated GABA and 4-hydroxybutyric acid in urine, liver and brain and clinically by ataxia, poor weight gain, myoclonic and convulsive seizures and convulsive status epilepticus similar to that seen in humans with known ALDH5A1 deficiency (12891658) , (11544478) .

 
 

ALDH 6 Family

ALDH6A1
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ALDH6A1 encodes a mitochondrial tetramer (~ 57.8 kDa subunits) also known as acetyl CoA-dependent methylmalonate semialdehyde dehydrogenase. This enzyme is responsible for catalyzing the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA (1527093) .

ALDH6A1 is unique among ALDH\'s because it is CoA-dependent. Like other ALDH\'s ALDH6A1 also retains esterase activity allowing it to hydrolyze p-nitrophenyl acetate with concomitant formation of an S-acyl enzyme and in the presence of CoA will generate acetyl-CoA (1527093) .

A deficiency in ALDH6A1 activity is characterized by elevated levels in urine of beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids (10947204) .

 
 

ALDH 7 Family

ALDH7A1
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ALDH7A1 encodes an ALDH also known as Antiquitin.

Human ALDH7A1 retains 60% homology to the green garden pea 26g protein involved in regulation of turgor pressure (8088832) . Due to the high degree of homology between proteins from the garden pea and the animal kingdom, it is assumed that the protein may have a significant indispensable physiological role in cell biology that related to the regulation of cellular turgor pressure. However, the exact physiological function of antiquitin remains to be determined.

Mammalian ALDH7A1 is thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation (11959129) .

Three pseudogenes of ALDH7A1 (ALDH7A1P1, ALDH7A1P2, and ALDH7A1P3) have been identified on separate chromosomes however the gene products have yet to be characterized.

 
 
ALDH7A2
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ALDH 8 Family

ALDH8A1
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ALDH8A1, a cytosolic enzyme (~53.4 kDa subunits), is considered to be a retinaldehyde dehydrogenase (RALDH4) that oxidizes retinaldehyde to retinoic acid. It plays a role in the 9-cis-retinoic acid biosynthesis pathway in vivo by converting 9-cis-retinal into the retinoid X receptor ligand 9-cis-retinoic acid.

ALDH8A1 has approximately a 40-fold higher activity with 9-cis-retinal than with all-trans-retinal (11007799) .

ALDH8A1 is the first known aldehyde dehydrogenase to show a preference for 9-cis-retinal relative to all-trans-retinal. Two transcript variants encoding distinct isoforms have been identified for this gene.

 
 

ALDH 9 Family

ALDH9A1
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ALDH9A1 was first purified from liver and characterized by Kurys (2925663) .

ALDH9A1 is a cytosolic tetramer (~53.8 kDa subunits) catalyzing the dehydrogenation of gamma-aminobutyraldehyde (Km = 5-14 uM) and aminoaldehydes derived from polyamines.

ALDH9A1 has also been identified as a betaine aldehyde dehydrogenase (7646513) .

ALDH9A1 is highly expressed in the liver, skeletal muscle, and kidney (2925663) , (8786138) but is undetectable in lung, placenta and brain (8786138) .

However, a variant of the liver isozyme is found in all regions of the brain with the highest levels present in the spinal cord (8645224) .

 
 

ALDH 10 Family

ALDH10A8
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ALDH10A9
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ALDH 11 Family

ALDH11A3
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ALDH11A4
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ALDH 12 Family

ALDH12A1
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ALDH 16 Family

ALDH16A1
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ALDH16A1 encodes for an enzyme that has yet to be characterized.

 
 

ALDH 18 Family

ALDH18A1
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The ALDH18A1 gene encodes for a bifunctional ATP- and NAD(P)H-dependent mitochondrial inner membrane enzyme (~87.1 kDa subunits) with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities (6933554) .

Traditionally known as Δ1-pyrroline-5-carboxylate synthetase, ALDH18A1 catalyzes the reduction of L-glutamate to Δ1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine.

Alternative splicing of ALDH18A1 generates two isoforms, a short and a long isoform that differ by a 2-amino acid insert at the N terminus of the gamma-glutamyl kinase active site (10037775) . The short isoform of ALDH18A1 has a high activity in the gut and catalyzes the essential step in arginine biosynthesis. It is inhibited by ornithine thereby providing a mechanism for the regulation of arginine synthesis. The long isoform is expressed in multiple tissues and is necessary for the synthesis of proline from glutamate. It is insensitive to ornithine inhibition (10037775) .

Individuals with an allelic variant in the ALDH18A1 gene (a G-to-A transition at position 251) exhibit hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and associated neurodegeneration, cataracts and connective tissue diseases secondary to the impaired functions of the long and short isoforms of the enzyme (11092761) .

 
 
ALDH18A2
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ALDH 22 Family

ALDH22A1
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