ALDH1A1 explained
Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene.[1] [2]
Function
This protein belongs to the aldehyde dehydrogenases family of proteins and is a member of the ALDH1 subfamily (including ALDH1A2, ALDH1A3, ALDH1B1, ALDH2). Aldehyde dehydrogenase isozymes are NAD(P)-dependent dehydrogenases that catalyze the oxidation of an aldehyde into the corresponding carboxylic acid while reducing NAD+ or NADP+. ALDH1A1 is the only ALDH1 isozyme known to oxidize 9-cis retinaldehyde into 9-cis retinoic acid[3] and thus serve as the only known activator of the rexinoid nuclear receptor pathway[4] . ALDH1A1 has also been described with activity against other substrates in living systems, including all-trans retinaldehyde[5] as well as oxazaphosphorine, a cyclophosphamide metabolite[6] . Unique among the ALDH1 isozymes, ALDH1A1 is known to possess esterase activity in biochemical studies[7], although it is unclear whether this is functionally relevant living tissues.
ALDH1A1 is expressed predominantly in metabolic tissues, including the liver, gastrointestinal tract, thyroid, pituitary gland, and adipose tissues[8] . ALDH1A1 is also expressed in the testes where its function in spermatogenesis is subordinate to and compensatory for ALDH1A2 in mice. ALDH1A1 is inhibited by Antabuse (disulfiram)[9], though the primary goal of disulfiram prescription is to inhibit ALDH2. The long clinical history of disulfiram use suggests that ALDH1A1 is not important to normal human physiology.
Clinical Significance
Obesity
The removal of ALDH1A1 in mice through genetic knockout results in viable animals that are fertile and healthy. The only validated phenotype of these mice is a resistance to high fat diet-induced obesity[10] and no impacts of ALDH1A1 removal have been described on fertility or neurological function. This biology closely replicates the clinical profile of Antabuse (disulfiram), and disulfiram has been shown to cause ALDH1A1-dependent weight loss in obese animals[11] . This has increased interest in disulfiram as an alternative weight loss therapy to Ozempic[12], yet the rare but potentially fatal liver-damaging effects of disulfiram due to its broad lack of selectivity as well as the alcohol-disulfiram reaction make it unattractive as a weight loss therapy[13] . Subsequent efforts to produce ALDH1A1-specific inhibitors have resulted in preclinical compounds that induce weight loss through increased metabolic activity[14] .
Errors Due to Historical Nomenclature
ALDH1A1 is often attributed with multiple biological roles as studies prior to human genome sequencing operated under the assumption that only one ALDH1 gene existed rather than the five isozymes that are annotated today[15] . Accordingly, ALDH1A1 is often attributed with a role in alcohol metabolism through oxidation of acetaldehyde, however, single nucleotide polymorphisms (SNPs) in this enzyme show little evidence of linkage to alcoholism in humans.[16] [17] Despite established naming conventions, many studies still incorrectly use ALDH1 to describe the family of isozymes. For instance, many cancers studies have been interpreted to report on ALDH1A1 activity when the actual protein was ALDH1A3[18] .
Species-Specific Expression
ALDH1A1 possesses unique taxon-specific traits across mammals. Found uniquely in rabbits compared to other mammals, ALDH1A1 appears to function as a corneal crystallin that helps to maintain the transparency of the cornea. In other species such as humans, this role is performed by ALDH3A1[19] . In beavers, the ALDH1A1 gene has undergone genomic expansion, resulting in approximately 10 copies of the genomic locus, which is putatively linked to a role in lipid balance[20] .
Further reading
- Walsh N, Dowling P, O'Donovan N, Henry M, Meleady P, Clynes M . Aldehyde dehydrogenase 1A1 and gelsolin identified as novel invasion-modulating factors in conditioned medium of pancreatic cancer cells . Journal of Proteomics . 71 . 5 . 561–71 . December 2008 . 18848913 . 10.1016/j.jprot.2008.09.002 .
- Barley K, Dracheva S, Byne W . Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder . Schizophrenia Research . 112 . 1–3 . 54–64 . July 2009 . 19447584 . 10.1016/j.schres.2009.04.019 . 39003080 .
- Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD . Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide . Pharmacogenetics and Genomics . 18 . 6 . 515–23 . June 2008 . 18496131 . 10.1097/FPC.0b013e3282fc9766 . 5604777 .
- Rodriguez FJ, Giannini C, Asmann YW, Sharma MK, Perry A, Tibbetts KM, Jenkins RB, Scheithauer BW, Anant S, Jenkins S, Eberhart CG, Sarkaria JN, Gutmann DH . 6 . Gene expression profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes . Journal of Neuropathology and Experimental Neurology . 67 . 12 . 1194–204 . December 2008 . 19018242 . 2730602 . 10.1097/NEN.0b013e31818fbe1e .
- Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW, Huang EH . Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer . Cancer Research . 69 . 20 . 8208–15 . October 2009 . 19808966 . 2776663 . 10.1158/0008-5472.CAN-09-1132 .
- Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY . Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations . Molecular Cancer Research . 6 . 7 . 1146–53 . July 2008 . 18644979 . 10.1158/1541-7786.MCR-08-0035 . free .
- Xiao T, Shoeb M, Siddiqui MS, Zhang M, Ramana KV, Srivastava SK, Vasiliou V, Ansari NH . 6 . Molecular cloning and oxidative modification of human lens ALDH1A1: implication in impaired detoxification of lipid aldehydes . Journal of Toxicology and Environmental Health. Part A . 72 . 9 . 577–84 . 2009 . 19296407 . 5645793 . 10.1080/15287390802706371 . 2009JTEHA..72..577X .
- Cañestro C, Catchen JM, Rodríguez-Marí A, Yokoi H, Postlethwait JH . Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes . PLOS Genetics . 5 . 5 . e1000496 . May 2009 . 19478994 . 2682703 . 10.1371/journal.pgen.1000496 . Gojobori . Takashi . free .
- Saito A, Kawamoto M, Kamatani N . Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects . Journal of Human Genetics . 54 . 6 . 317–23 . June 2009 . 19343046 . 10.1038/jhg.2009.31 . free .
- Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, Chen DT, Tai LK, Yung MC, Chang SC, Ku HH, Chiou SH, Lo WL . 6 . Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer . Biochemical and Biophysical Research Communications . 385 . 3 . 307–13 . July 2009 . 19450560 . 10.1016/j.bbrc.2009.05.048 .
- Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob G, Richardson HN, Kechris K, Bell RL, Hübner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL . 6 . Genetical genomic determinants of alcohol consumption in rats and humans . BMC Biology . 7 . 70 . October 2009 . 19874574 . 2777866 . 10.1186/1741-7007-7-70 . free .
- Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, Tamaki Y, Terada N, Noguchi S . 6 . Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression . Cancer Science . 100 . 6 . 1062–8 . June 2009 . 19385968 . 10.1111/j.1349-7006.2009.01151.x . 22510108 . free . 11158415 .
- Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD . Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin . Pharmacogenetics and Genomics . 18 . 11 . 1009–15 . November 2008 . 18854779 . 10.1097/FPC.0b013e328313aaa4 . 2979088 .
- Wan C, Shi Y, Zhao X, Tang W, Zhang M, Ji B, Zhu H, Xu Y, Li H, Feng G, He L . 6 . Positive association between ALDH1A2 and schizophrenia in the Chinese population . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 33 . 8 . 1491–5 . November 2009 . 19703508 . 10.1016/j.pnpbp.2009.08.008 . 32862839 .
- Low SK, Kiyotani K, Mushiroda T, Daigo Y, Nakamura Y, Zembutsu H . Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients . Journal of Human Genetics . 54 . 10 . 564–71 . October 2009 . 19696793 . 10.1038/jhg.2009.79 . free .
- Moore SM, Liang T, Graves TJ, McCall KM, Carr LG, Ehlers CL . Identification of a novel cytosolic aldehyde dehydrogenase allele, ALDH1A1*4 . Human Genomics . 3 . 4 . 304–7 . July 2009 . 19706361 . 2885287 . 10.1186/1479-7364-3-4-304 . free .
- Chang B, Liu G, Xue F, Rosen DG, Xiao L, Wang X, Liu J . ALDH1 expression correlates with favorable prognosis in ovarian cancers . Modern Pathology . 22 . 6 . 817–23 . June 2009 . 19329942 . 2692456 . 10.1038/modpathol.2009.35 .
- Lind PA, Eriksson CJ, Wilhelmsen KC . The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in harmful alcohol consumption in a Finnish population . Human Genomics . 3 . 1 . 24–35 . September 2008 . 19129088 . 3525184 . 10.1186/1479-7364-3-1-24 . free .
- Moreb JS, Baker HV, Chang LJ, Amaya M, Lopez MC, Ostmark B, Chou W . ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells . Molecular Cancer . 7 . 1 . 87 . November 2008 . 19025616 . 2605459 . 10.1186/1476-4598-7-87 . free .
- Dancik GM, Varisli L, Vlahopoulos SA . The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia. . International Journal of Molecular Sciences . 2023 . 24 . 11 . 9372 . 10.3390/ijms24119372 . 37298333 . 10253856 . free .
Notes and References
- Pereira F, Rosenmann E, Nylen E, Kaufman M, Pinsky L, Wrogemann K . The 56 kDa androgen binding protein is an aldehyde dehydrogenase . Biochemical and Biophysical Research Communications . 175 . 3 . 831–8 . March 1991 . 1709013 . 10.1016/0006-291X(91)91640-X .
- Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A . Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2 . Proceedings of the National Academy of Sciences of the United States of America . 82 . 11 . 3771–5 . June 1985 . 2987944 . 397869 . 10.1073/pnas.82.11.3771 . 1985PNAS...82.3771H . free .
- Labrecque . J . Dumas . F . Lacroix . A . Bhat . P V . 1995-01-15 . A novel isoenzyme of aldehyde dehydrogenase specifically involved in the biosynthesis of 9-cis and all-trans retinoic acid . Biochemical Journal . 305 . 2 . 681–684 . 10.1042/bj3050681 . 0264-6021 . 1136415 . 7832787.
- Esposito . Mark . Amory . John K. . Kang . Yibin . 2024-08-12 . The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes . Journal of Experimental Medicine . 221 . 9 . e20240519 . 10.1084/jem.20240519 . 39133222 . 11318670 . 0022-1007.
- Topping . Traci . Griswold . Michael D. . 2022 . Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis . Frontiers in Endocrinology . 13 . 871225 . 10.3389/fendo.2022.871225 . free . 1664-2392 . 9097449 . 35574006.
- Sládek . Norman E. . Kollander . Rahn . Sreerama . Lakshmaiah . Kiang . David T. . 2002-04-01 . Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study . Cancer Chemotherapy and Pharmacology . en . 49 . 4 . 309–321 . 10.1007/s00280-001-0412-4 . 1432-0843.
- Koppaka . Vindhya . Thompson . David C. . Chen . Ying . Ellermann . Manuel . Nicolaou . Kyriacos C. . Juvonen . Risto O. . Petersen . Dennis . Deitrich . Richard A. . Hurley . Thomas D. . Vasiliou . Vasilis . 2012-07-01 . Sibley . David R. . Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application . Pharmacological Reviews . en . 64 . 3 . 520–539 . 10.1124/pr.111.005538 . 0031-6997 . 3400832 . 22544865.
- Web site: Tissue expression of ALDH1A1 - Summary - The Human Protein Atlas . 2024-12-03 . www.proteinatlas.org.
- Omran . Ziad . 2022-01-12 . Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors . Molecules (Basel, Switzerland) . 27 . 2 . 480 . 10.3390/molecules27020480 . free . 1420-3049 . 8778300 . 35056791.
- Kiefer . Florian W. . Vernochet . Cecile . O'Brien . Patrick . Spoerl . Steffen . Brown . Jonathan D. . Nallamshetty . Shriram . Zeyda . Maximilian . Stulnig . Thomas M. . Cohen . David E. . Kahn . C. Ronald . Plutzky . Jorge . June 2012 . Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue . Nature Medicine . en . 18 . 6 . 918–925 . 10.1038/nm.2757 . 1546-170X . 3792792 . 22561685.
- Bernier . Michel . Mitchell . Sarah J. . Wahl . Devin . Diaz . Antonio . Singh . Abhishek . Seo . Wonhyo . Wang . Mingy . Ali . Ahmed . Kaiser . Tamzin . Price . Nathan L. . Aon . Miguel A. . Kim . Eun-Young . Petr . Michael A. . Cai . Huan . Warren . Alessa . 2020-08-04 . Disulfiram Treatment Normalizes Body Weight in Obese Mice . Cell Metabolism . English . 32 . 2 . 203–214.e4 . 10.1016/j.cmet.2020.04.019 . 1550-4131 . 7957855 . 32413333.
- Web site: 2020-05-14 . Repurposed drug helps obese mice lose weight, improve metabolic function . 2024-12-03 . National Institutes of Health (NIH) . EN.
- Web site: Disulfiram: Package Insert / Prescribing Information . 2024-12-03 . Drugs.com . en.
- Haenisch . Michael . Treuting . Piper M. . Brabb . Thea . Goldstein . Alex S. . Berkseth . Kathryn . Amory . John K. . Paik . Jisun . 2018-01-01 . Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity . Obesity Research & Clinical Practice . 12 . 1 . 93–101 . 10.1016/j.orcp.2017.08.003 . 1871-403X . 5816716 . 28919001.
- Vasiliou . V. . Bairoch . A. . Tipton . K. F. . Nebert . D. W. . August 1999 . Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping . Pharmacogenetics . 9 . 4 . 421–434 . 0960-314X . 10780262.
- Sherva R, Rice JP, Neuman RJ, Rochberg N, Saccone NL, Bierut LJ . Associations and interactions between SNPs in the alcohol metabolizing genes and alcoholism phenotypes in European Americans . Alcoholism: Clinical and Experimental Research . 33 . 5 . 848–57 . May 2009 . 19298322 . 2892966 . 10.1111/j.1530-0277.2009.00904.x .
- Liu J, Zhou Z, Hodgkinson CA, Yuan Q, Shen PH, Mulligan CJ, Wang A, Gray RR, Roy A, Virkkunen M, Goldman D, Enoch MA . 6 . Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations . Alcoholism: Clinical and Experimental Research . 35 . 2 . 304–16 . February 2011 . 21083667 . 3026908 . 10.1111/j.1530-0277.2010.01346.x .
- Ginestier . Christophe . Hur . Min Hee . Charafe-Jauffret . Emmanuelle . Monville . Florence . Dutcher . Julie . Brown . Marty . Jacquemier . Jocelyne . Viens . Patrice . Kleer . Celina G. . Liu . Suling . Schott . Anne . Hayes . Dan . Birnbaum . Daniel . Wicha . Max S. . Dontu . Gabriela . 2007-11-15 . ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome . Cell Stem Cell . English . 1 . 5 . 555–567 . 10.1016/j.stem.2007.08.014 . 1934-5909 . 2423808 . 18371393.
- Jester JV, Moller-Pedersen T, Huang J, Sax CM, Kays WT, Cavangh HD, Petroll WM, Piatigorsky J . 6 . The cellular basis of corneal transparency: evidence for 'corneal crystallins' . Journal of Cell Science . 112 . 5 . 613–22 . March 1999 . 9973596 . 10.1242/jcs.112.5.613 . 112 .
- Zhang . Quanwei . Tombline . Gregory . Ablaeva . Julia . Zhang . Lei . Zhou . Xuming . Smith . Zachary . Zhao . Yang . Xiaoli . Alus M. . Wang . Zhen . Lin . Jhih-Rong . Jabalameli . M. Reza . Mitra . Joydeep . Nguyen . Nha . Vijg . Jan . Seluanov . Andrei . 2021-11-09 . Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation . Cell Reports . 37 . 6 . 109965 . 10.1016/j.celrep.2021.109965 . 2211-1247 . 8656434 . 34758328.