Biology:ALDH1A1

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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 retinoid 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.[5] ALDH1A1 is inhibited by Antabuse (disulfiram),[9] though the primary pharmacologic target of disulfiram in clinical use is ALDH2. The long clinical history of disulfiram use suggests that ALDH1A1 is not important to normal human physiology. Tumors, specifically in ovarian cancer are found to have a high expression of ALDH1A1[10].ALDH1A1 is found to cause resistance to chemotherapy.[11]

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[12] while whole body ALDH1A1 removal does not affect fertility or neurological function. This biology closely replicates the clinical profile of Antabuse (disulfiram). Disulfiram and other ALDH1A1 inhibitors have been shown to cause ALDH1A1-dependent weight loss in obese animals.[13] This has increased interest in disulfiram as an alternative weight loss therapy to Ozempic,[14] 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.[15] Subsequent efforts to produce ALDH1A1-specific inhibitors have resulted in preclinical compounds that induce weight loss through increased metabolic activity.[16]

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.[17] 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.[18][19] Despite established naming conventions,[17] 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.[20]

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.[21] 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.[22]

References

  1. ↑ "The 56 kDa androgen binding protein is an aldehyde dehydrogenase". Biochemical and Biophysical Research Communications 175 (3): 831–8. March 1991. doi:10.1016/0006-291X(91)91640-X. PMID 1709013. Bibcode: 1991BBRC..175..831P. 
  2. ↑ "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. doi:10.1073/pnas.82.11.3771. PMID 2987944. Bibcode: 1985PNAS...82.3771H. 
  3. ↑ 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. doi:10.1042/bj3050681. ISSN 0264-6021. PMID 7832787. PMC 1136415. https://portlandpress.com/biochemj/article-abstract/305/2/681/30791/A-novel-isoenzyme-of-aldehyde-dehydrogenase?redirectedFrom=fulltext. 
  4. ↑ 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). doi:10.1084/jem.20240519. ISSN 0022-1007. PMID 39133222. PMC 11318670. https://rupress.org/jem/article/221/9/e20240519/276897/The-pathogenic-role-of-retinoid-nuclear-receptor. 
  5. ↑ 5.0 5.1 Topping, Traci; Griswold, Michael D. (2022). "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology 13. doi:10.3389/fendo.2022.871225. ISSN 1664-2392. PMID 35574006. 
  6. ↑ 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" (in en). Cancer Chemotherapy and Pharmacology 49 (4): 309–321. doi:10.1007/s00280-001-0412-4. ISSN 1432-0843. PMID 11914911. https://link.springer.com/article/10.1007/s00280-001-0412-4. 
  7. ↑ Koppaka, Vindhya; Thompson, David C.; Chen, Ying; Ellermann, Manuel; Nicolaou, Kyriacos C.; Juvonen, Risto O.; Petersen, Dennis; Deitrich, Richard A. et al. (2012-07-01). Sibley, David R.. ed. "Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application" (in en). Pharmacological Reviews 64 (3): 520–539. doi:10.1124/pr.111.005538. ISSN 0031-6997. PMID 22544865. PMC 3400832. https://pharmrev.aspetjournals.org/content/64/3/520. 
  8. ↑ "Tissue expression of ALDH1A1 - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000165092-ALDH1A1/tissue. 
  9. ↑ Omran, Ziad (2022-01-12). "Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors". Molecules (Basel, Switzerland) 27 (2): 480. doi:10.3390/molecules27020480. ISSN 1420-3049. PMID 35056791. 
  10. ↑ Muralikrishnan, Vaishnavi (2020). "Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies". Cancers 12 (4): 961. doi:10.3390/cancers12040961. PMID 32295073. 
  11. ↑ Muralikrishnan, Vaishnavi (2022). "A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer". Cancers 14 (14): 3437. doi:10.3390/cancers14143437. PMID 35884498. 
  12. ↑ Kiefer, Florian W.; Vernochet, Cecile; O'Brien, Patrick; Spoerl, Steffen; Brown, Jonathan D.; Nallamshetty, Shriram; Zeyda, Maximilian; Stulnig, Thomas M. et al. (June 2012). "Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue" (in en). Nature Medicine 18 (6): 918–925. doi:10.1038/nm.2757. ISSN 1546-170X. PMID 22561685. 
  13. ↑ Bernier, Michel; Mitchell, Sarah J.; Wahl, Devin; Diaz, Antonio; Singh, Abhishek; Seo, Wonhyo; Wang, Mingy; Ali, Ahmed et al. (2020-08-04). "Disulfiram Treatment Normalizes Body Weight in Obese Mice" (in English). Cell Metabolism 32 (2): 203–214.e4. doi:10.1016/j.cmet.2020.04.019. ISSN 1550-4131. PMID 32413333. 
  14. ↑ "Repurposed drug helps obese mice lose weight, improve metabolic function" (in EN). 2020-05-14. https://www.nih.gov/news-events/news-releases/repurposed-drug-helps-obese-mice-lose-weight-improve-metabolic-function. 
  15. ↑ "Disulfiram: Package Insert / Prescribing Information" (in en). https://www.drugs.com/pro/disulfiram.html. 
  16. ↑ 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. doi:10.1016/j.orcp.2017.08.003. ISSN 1871-403X. PMID 28919001. 
  17. ↑ 17.0 17.1 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. ISSN 0960-314X. PMID 10780262. 
  18. ↑ "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. doi:10.1111/j.1530-0277.2009.00904.x. PMID 19298322. 
  19. ↑ "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. doi:10.1111/j.1530-0277.2010.01346.x. PMID 21083667. 
  20. ↑ Ginestier, Christophe; Hur, Min Hee; Charafe-Jauffret, Emmanuelle; Monville, Florence; Dutcher, Julie; Brown, Marty; Jacquemier, Jocelyne; Viens, Patrice et al. (2007-11-15). "ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome" (in English). Cell Stem Cell 1 (5): 555–567. doi:10.1016/j.stem.2007.08.014. ISSN 1934-5909. PMID 18371393. 
  21. ↑ "The cellular basis of corneal transparency: evidence for 'corneal crystallins'". Journal of Cell Science. 112 112 (5): 613–22. March 1999. doi:10.1242/jcs.112.5.613. PMID 9973596. 
  22. ↑ Zhang, Quanwei; Tombline, Gregory; Ablaeva, Julia; Zhang, Lei; Zhou, Xuming; Smith, Zachary; Zhao, Yang; Xiaoli, Alus M. et al. (2021-11-09). "Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation". Cell Reports 37 (6). doi:10.1016/j.celrep.2021.109965. ISSN 2211-1247. PMID 34758328. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.




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