The ALDH gene superfamily is found in Archaea, Eubacteria and Eukarya, indicating a vital role for this family throughout evolutionary history (Jackson et al., 2011). A standardized gene nomenclature system based on divergent evolution and amino acid identity was established for the ALDH superfamily in The Ninth International Symposium on Enzymology and Molecular Biology of Carbonyl Metabolism, in 1998 (Figure 2) (Marchitti et al., 2008). There are 19 known functional aldehyde dehydrogenase (ALDH) genes and many pseudogenes in the human genome (Tomita et al., 2016). ALDH1 family has six members including ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, and ALDH1L2 (C. K. Yang et al., 2017). Since vertebrate ALDH1A1, ALDH1A2 and ALDH1A3 subunit sequences are highly conserved: subsequent gene duplication events are thought to generate ALDH1A1, ALDH1A2 and ALDH1A3 genes in most vertebrate genomes, except some bony fish (Holmes, 2015). ALDH1A1 homologs are present in most vertebrae species, but are absent in Zebra fish and other fishes in the teleost lineage (Table 1) (Jackson et al., 2011).

Gene Species	Gene Symbol	Identity (%) DNA
H.sapiens	ALDH1A1
vs. P.troglodytes	ALDH1A1	99,5
vs. M.mulatta	ALDH1A1	97,9
vs. C.lupus	ALDH1A1	88,4
vs. B.taurus	ALDH1A1	90,2
vs. M.musculus	Aldh1a1	84,6
vs. R.norvegicus	Aldh1a1	83,9
vs. G.gallus	ALDH1A1	79,4
vs. X.tropicalis	aldh1a1	74,4
vs. E.gossypii	AGOS_ADR417W	54,1
vs. A.thaliana	ALDH2C4	57,6
vs. O.sativa	Os01g0591000	56
vs. O.sativa	Os01g0591300	55,5

Table 1. Pairwise alignment of ALDH1A1 gene (in distance from human) (HomoloGene, NCBI).

The ALDH1A1 gene is a protein coding gene. The gene covers 52656 bp, from 72900662 to 72953317 (NC_000009.12). It is located on the plus strand spanning 13 exons (GRCh38, NCBI Homo sapiens Annotation Release 109).

This gene has 7 transcripts (splice variants), 161 orthologues and 18 paralogues depending on Ensembl release 95-January 2019 (Table 2). ENST00000297785.7 (ALDH1A1-201) transcript has 13 exons, ENST00000376939.5 (ALDH1A1-202) and ENST00000419959.5 (ALDH1A1-203) transcripts have 8 exons, and ENST00000446946.1 (ALDH1A1-204) transcript has 7 exons (Figure 3).

Name	Transcript ID	bp	CCDS	RefSeq
ALDH1A1-201	ENST00000297785.7	2107	CCDS6644	NM_000689
ALDH1A1-202	ENST00000376939.5	822	-	-
ALDH1A1-203	ENST00000419959.5	806	-	-
ALDH1A1-204	ENST00000446946.1	805	-	-
ALDH1A1-205	ENST00000482210.5	879	-	-
ALDH1A1-206	ENST00000493113.1	604	-	-
ALDH1A1-207	ENST00000493311.1	209	-	-

Table 2. Transcripts of human ALDH1A1 gene (Ensembl release 95-January 2019)
Studies in human K562 erythroleukemia and Hep3B hepatoma cells showed that the ALDH1A1 promoter contains a positive regulatory region (-91 to +53 bp to the transcription start site) with a CCAAT box as a major cisacting element (Alam et al., 2013). Among CCAAT-recognizing transcription factors, nuclear factor YA ( NFYA) was shown to be involved in ALDH1A1 transcription. Mamat et al. found that in cooperation with POU2F1 (Oct-1), alternatively spliced isoforms of NFYA plays an important role in ALDH1A1 expression in endometrial adenocarcinoma (Mamat et al., 2011). In mouse hepatoma cells, RARA transactivates the Aldh1a1 promoter by binding to the RARE region, located between -91 and -75 bp. Moreover, CEBPB has been demonstrated to transactivate the ALDH1A1 promoter by interacting with the CCAAT box that resides at -75 to -71 bp adjacent to the RARE (Alam et al., 2013).

Not identified.

Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an heterotetramer enzyme that is encoded by the human ALDH1A1 gene. Human ALDH1A1 is 501 amino acids in length (Table 3). ALDH1A1 protein similarity across species are given in Table 4.

Name	Transcript ID	bp	Protein	Charge	Isoelectric Point	Molecular Weight	CCDS	UniProt	RefSeq
ALDH1A1-201	ENST00000297785.7	2107	501aa	1,0	6,6811	54,861.84 g/mol	CCDS6644	P00352 V9HW83	NM_000689  NP_000680
ALDH1A1-202	ENST00000376939.5	822	230aa	-0,5	6,2427	25,314.22 g/mol	-	Q5SYQ9	-
ALDH1A1-203	ENST00000419959.5	806	238aa	-1,0	6.1061	26,097.05 g/mol	-	Q5SYQ8	-
ALDH1A1-204	ENST00000446946.1	805	203aa	-1,0	5,8174	22,654.11 g/mol	-	Q5SYQ7	-

Table 3. Protein products of human ALDH1A1 gene (Ensembl release 95-January 2019)

Gene Species	Gene Symbol	Identity (%) Protein
H.sapiens	ALDH1A1
vs. P.troglodytes	ALDH1A1	100
vs. M.mulatta	ALDH1A1	98,8
vs. C.lupus	ALDH1A1	89
vs. B.taurus	ALDH1A1	91,2
vs. M.musculus	Aldh1a1	87
vs. R.norvegicus	Aldh1a1	86,4
vs. G.gallus	ALDH1A1	84,2
vs. X.tropicalis	aldh1a1	78,2
vs. E.gossypii	AGOS_ADR417W	50,7
vs. A.thaliana	ALDH2C4	52
vs. O.sativa	Os01g0591000	53,8
vs. O.sativa	Os01g0591300	51,8

Table 4. Pairwise alignment of ALDH1A1 protein sequences (in distance from human) (HomoloGene, NCBI)

The human ALDH1 family shares over 60% protein sequence identity and has six subfamily members (C. K. Yang et al., 2017). Crystal structures of mammalian ALDH enzymes have shown that each subunit contains three domains: (1) an NAD(P) ⁺ cofactorbinding domain, (2) a catalytic domain, and (3) a bridging domain. A funnel passage leading to the catalytic pocket is found at the interface of these domains. ALDH specificity toward particular aldehyde substrates is thought to be caused by the upper portion of the funnel which is composed of residues from all three domains. The lower portion of the funnel appears to be the catalytic site where hydride transfer from substrate to cofactor occur, is composed of highly conserved residues (Marchitti et al., 2008) (Figure 6).

ALDH1A1 is a highly conserved homotetramer somatic cell plasma protein, expressed in numerous tissues, including liver, kidney, red blood cells, skeletal muscle, lung, breast, lens, stomach, brain, pancreas, testis, prostate, ovary (Jackson et al., 2011; Mamat et al., 2011). The detailed RNA and protein expression information can be found in: Human Protein Atlas (https://www.proteinatlas.org/ENSG00000165092-ALDH1A1/tissue).

ALDH1A1 is present in the cytosol. Interestingly, Kahlert et al. observed nuclear expression of ALDH1A1 in a small subgroup of patients with colon cancer and rectal cancer, and found that in colon cancer patients, nuclear expression of ALDH1A1 was significantly associated with shortened overall survival (Kahlert et al., 2012).

In retinol metabolism (Figure 4), retinol is oxidized by retinol dehydrogenases (RD) to retinal. Later on, retinal is oxidized to retinoic acid (RA) in a reaction catalyzed by the human ALDH isoenzymes ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1The metabolized product RA includes all-trans RA (ATRA), 9-cis RA, and 13-cis RA. The ALDH isoforms, especially ALDH1A1, have an affinity for ATRA and 9-cis RA. RA diffuses into the nucleus and acts as a ligand for the retinoic acid receptors (RARA, RARB, RARG) and retinoic X receptors ( RXRA, RXRB, RXRG). Then, the ligand-receptor complex binds to the retinoic acid response element (RARE) in the promoter of target genes and therefore regulates differentiation, apoptosis and/or cell cycle arrest in a context-dependent manner (Marcato et al., 2011b; Tomita et al., 2016). RXRA^-/- mice were shown to have decreased liver ALDH1A1 levels, suggesting that RA binding is an activating factor in ALDH1A1 gene expression (Gyamfi, 2006). RA is required for testicular development and ALDH1A1 is absent in genital tissues of humans with androgen receptor-negative testicular feminization. Being an androgen binding protein, ALDH1A1 expression is thought to be regulated also by the androgen receptor (Li et al., 2010; Marchitti et al., 2008).
Aldehyde dehydrogenase (ALDH) enzyme family plays an important role in cellular signal transmission and protection by catalyzing the oxidation of aldehydes (Alam et al., 2013). ALDH1A1 mainly contributes to the biosynthesis of retinoic acid (RA) from vitamin A (Van Der Waals et al., 2018). Inside the cell, Retinol (vitamin A) is oxidized to retinal by retinal dehydrogenases. The retinal is then oxidized to RA in a reaction catalyzed with ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1 (Tomita et al., 2016). The RA enters the cell nucleus and binds and activates RA receptors (RARs) or retinoid X receptors (RXRs) to regulate gene expression (Zhao et al., 2014).
ALDH1A1 also plays a role in acetaldehyde metabolism. Acetaldehyde is the first product of ethanol metabolism. Alcohol, taken with alcohol consumption, is converted to acetaldehyde by alcohol dehydrogenase (ADH), catalase and cytochrome P450 2E1. Then, acetaldehyde is metabolized to acetates by ALDH2 and ALDH1A1. Indeed, low ALDH1A1 activity is suggested to be related to alcohol sensitivity in some Caucasian populations ("Identification And Characterisation Of Alcohol-Induced Flushing In Caucasian Subjects", 2017). Moreover, decreased levels of ALDH1A1 were shown in RXRA^{-/-w/sup> mice, which were more susceptible to alcoholic liver injury (Gyamfi, 2006), while increased ALDH1A1 expression found in brains of alcohol-avoiding DBA/2 mice (Bhave et al., 2006).
ALDH1A1 is predominantly expressed by a subgroup of dopaminergic (DA) neurons in the midbrain (Maring et al., 1985). In DA neurons, ALDH1A1 mediates the oxidation of the cytotoxic dopamine intermediate, 3,4-dihydroxyphenylacetaldehyde (DOPAL), to the less reactive 3,4-dihydroxyphenylacetic acid (DOPAC), and thereby protects the DA neurons from toxicity (Pan et al., 2019). Very recently, ALDH1A1 was reported to mediate the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Kim et al., 2015) in DA neurons, where co-release of dopamine and GABA regulates alcohol consumption and preference (Pan et al., 2019). In addition, as a metabolic product of ALDH1A1, RA is known to play a crucial role in neuronal patterning, differentiation, and survival (Pan et al., 2019).
In addition to its role in aldehyde metabolism, ALDH1A1 possesses esterase activity. Collard et al. proposed ALDH1A1 being the major if not the only enzyme responsible for the oxidation of 3-deoxyglucosone to 2-keto-3-deoxygluconate (Collard et al., 2007).
ALDHs are generally categorized as detoxification enzymes. ALDH1A1 was found to offer cellular protection against cytotoxic drugs and implicated in drug-resistance in chemotherapy (Tomita et al., 2016). ALDH1A1 activity has been reported to provide cellular protection against some oxazaphosphorine anticancer drugs, such as cyclophosphamide (CP) and ifosfamide, by detoxifying their major active aldehyde metabolites (Hilton, 1984; Wang et al., 2017).
ALDH1A1 also plays a vital role as a marker of stem cells and cancer stem cells. Experimental data indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue and cancer type specific. On the other hand, although elevated ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, high ALDH1 and ALDH1A1 levels are not always correlated with highly malignant phenotypes and poor clinical outcome in a range of cancers (Tomita et al., 2016). It is suggested that ALDH1A1 can be a useful marker for cancer stem cells derived from tumors that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon, and stomach (Tomita et al., 2016; Xing et al., 2014).
ALDH1A1 also plays a key role in the cellular defense against oxidative stress: ALDH activity is required to maintain sufficiently low Reactive Oxygen Species (ROS) level. Human ALDH1A1 was shown to efficiently oxidize lipid peroxidation-derived aldehydes, like 4-Hydroxynonenal (4-HNE), hexanal, and Malondialdehyde (MDA) (MANZER et al., 2003), and Aldh1a1 knock-out mouse models demonstrated that ALDH1A1 plays a crucial role in protecting the mouse eye lens and cornea by detoxifying lipid peroxidation-derived aldehydes and preventing cataract formation induced by oxidative stresses (Mice et al., 2008).
In addition to its catalytic functions, ALDH1A1 has also non-catalytic roles. Similar with other ALDHs, ALDH1A1 acts as corneal and lens crystallins in mammalian eye tissue and contributes to the transparent and refractive properties of the eye (Vasiliou et al., 2013), as well as protects the eye from tissue damage as mentioned earlier. Finally, since ALDH1A1 can bind thyroid hormone and its expression is induced by estrogens, it is suggested that the enzyme may be regulated by or involved in hormone signaling (Marchitti et al., 2008).}

A list of ALDH1A1 mutations in cancer can be found in: COSMIC, the Catalogue of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ALDH1A1
Consequences of indicated ALDH1A1 mutations are necessary to evaluate.