ALDH1A1 (Aldehyde Dehydrogenase 1 family member A1)

Alias (NCBI)	ALDC
	ALDH-E1
	ALDH1
	ALDH11
	HEL-9
	HEL-S-53e
	HEL12
	PUMB1
	RALDH1
HGNC (Hugo)	ALDH1A1
HGNC Alias symb	RALDH1
HGNC Alias name	retinaldehyde dehydrogenase 1
HGNC Previous name	PUMB1
	ALDH1
HGNC Previous name	"aldehyde dehydrogenase 1 family, member A1"
LocusID (NCBI)	216
Atlas_Id	53077
Location	9q21.13  [Link to chromosome band 9q21]
Location_base_pair	Starts at 72900671 and ends at 72953053 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ALDH1A1.png]
Local_order	Starts at 72900662 and ends at 72953317 (according to GRCh38) (Figure 1).
	Figure 1. Genomic location of human ALDH1A1 (Chromosome 9 - NC_000009.12, GRCh38.p12 Primary Assembly)

Note	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).
	Figure 2. ALDH Nomenclature
	Figure 3. Display of human ALDH1A1 gene transcript exons (Ensembl release 95 - January 2019)
Description	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).
Transcription	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).
Pseudogene	Not identified.

Note	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)
Description	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).
Expression	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).
Localisation	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).
Function	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).
	Figure 4. Retinoic acid signaling pathway: Retinoic acid (RA), generated by ALDHs, can function in the paracrine or endocrine manner by diffusing into neighbouring cells or the nucleus. In the nucleus, RA binds to heterodimers of the retinoic acid receptor (RAR) and retinoid x receptor (RXR). Activated receptor complexes induce transcription of target genes by binding to retinoic acid response elements (RAREs).
	Figure 5. ALDH1A1 regulation and function: Once inside the cytoplasm, retinol is oxidized to retinal, then retinal is oxidized to RA by several isoforms of ALDH. RA binds to dimers of RARA and RXRs to induce the expression of its downstream target genes. RA can bind to dimers of RXRs and ESR1 (ERα) as well as induce the expression of MYC and CCND1 (cyclin D1) in ERα-expressing cells. In addition to RA binding to the RAR, CEBPB and OCT1 binding to the ALDH1A1 promoter enhances the ALDH1A1 transcription. NFYA was also shown to activate ALDH1A1 transcription while DDB2 was shown to suppress ALDH1A1 expression by preventing CEBPB binding to the promoter. The details can be found in the text. The figure is modified from Tomita et al. (Tomita et al., 2016)).
	Figure 6. Structure of human ALDH1A1: Structure of human ALDH1A1 determined using X-ray diffraction (PDB ID: 4WJ9) (Morgan and Hurley, 2015; Rose et al., 2018).

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