ALDH1A3 explained

Aldehyde dehydrogenase 1 family, member A3 (ALDH1a3), also known as retinaldehyde dehydrogenase 3 (RALDH3) or as ALDH6 in earlier published studies, is an enzyme that in humans is encoded by the ALDH1A3 gene.,[1]

Function

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+. ALDH1a3 oxidizes all-trans retinaldehyde into all-trans retinoic acid and thus serves as the final catalytic step in the activation of the retinoid nuclear receptor (RAR) pathway.[2] While ALDH1a3 and related isozymes are known to utilize many aldehyde substrates in biochemical experiments,[3] genetic and functional analysis demonstrates that ALDH1a3 functions only to oxidize all-trans retinaldehyde in living systems.[4] ALDH1a3 exists as a homotetramer[5] with cytosolic localization. It is not known to have any function in healthy adult tissues.[6] ALDH1a3 contains a catalytic cysteine residue which is only minimally inhibited by the ALDH2-targeted drug disulfiram. While no specific ALDH1a3 inhibitors have been tested in humans, the pan-ALDH1 inhibitor Win18446 (Fertilysin) was tested in humans for 23 weeks with no observed adverse effects.[7]

The function of ALDH1a3 is known to be restricted to early fetal development and is dispensable in either adult mammals[8] or healthy adult humans. ALDH1a3 is a potential therapeutic target in type 2 diabetes.[9] cardiovascular disorders,[10] [11] and cancer[12] where its expression is amplified and it has known pathogenic activity. ALDH1a3 is not necessary for spermatogenesis[13] or the visual cycle.

Clinical significance

Type 2 Diabetes

ALDH1a3 is established as a primary marker of failing beta cells in the pancreas, both in human type 2 diabetes patients[14] and mouse models of diabetes.[15] ALDH1a3 expression has been shown to suppress insulin secretion and increase glucagon production in laboratory experiments.[16] ALDH1a3 was more recently established as a driver of beta cell failure and thus type 2 diabetes in a retinoid-dependent mechanism. Genetic and pharmacologic experiments with recently described ALDH1a3 inhibitors suggest that ALDH1a3 is a potential target to reverse beta cell decline in type 2 diabetes and thus restore insulin independence.[17]

Cardiovascular Disorders

ALDH1a3 is activated in injured or inflamed vascular smooth muscle cells in the context of pulmonary arterial hypertension and neointimal hyperplasia. Activation of ALDH1a3 in these cells causes vascular wall thickening and narrowing of pulmonary arteries, leading to disease progression. Chronic activation of the retinoid nuclear receptor causes increases in mortality due to heart failure.[18]

Cancer

ALDH1a3 is expressed in many cancer types while it is not expressed in the normal cells from which those cancers are derived. There is extensive literature evidence for the selective enrichment of ALDH1a3 across many cancers, including melanoma,[19] glioblastoma,[20] lung cancer,[21] pancreatic cancer,[22] breast cancer,[23] sarcomas and many other cancer types. While the putative role of ALDH1a3 in each of these cancers is via activation of the retinoid pathway, many studies disagree on its mechanism. A unifying theory for its activity in cancer was described through the generation of all-trans retinoic acid that acts in a paracrine manner on immune cells in the tumor microenvironment.

Further reading

Notes and References

  1. Hsu LC, Chang WC, Hiraoka L, Hsieh CL . Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6 . Genomics . 24 . 2 . 333–341 . November 1994 . 7698756 . 10.1006/geno.1994.1624 . free .
  2. Esposito M, Amory JK, Kang Y . The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes . The Journal of Experimental Medicine . 221 . 9 . e20240519 . September 2024 . 39133222 . 11318670 . 10.1084/jem.20240519 .
  3. Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V . Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application . Pharmacological Reviews . 64 . 3 . 520–539 . July 2012 . 22544865 . 3400832 . 10.1124/pr.111.005538 . Sibley DR .
  4. Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB . A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment . Proceedings of the National Academy of Sciences of the United States of America . 100 . 24 . 14036–14041 . November 2003 . 14623956 . 283541 . 10.1073/pnas.2336223100 . free . 2003PNAS..10014036D .
  5. Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S . Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid . Scientific Reports . 6 . 1 . 35710 . October 2016 . 27759097 . 5069622 . 10.1038/srep35710 .
  6. Web site: Tissue expression of ALDH1A3 - Summary - The Human Protein Atlas . 2024-12-03 . www.proteinatlas.org.
  7. Heller CG, Moore DJ, Paulsen CA . Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines . Toxicology and Applied Pharmacology . 3 . 1 . 1–11 . January 1961 . 13713106 . 10.1016/0041-008X(61)90002-3 . 1961ToxAP...3....1H .
  8. Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB . A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment . Proceedings of the National Academy of Sciences of the United States of America . 100 . 24 . 14036–14041 . November 2003 . 14623956 . 283541 . 10.1073/pnas.2336223100 . free . 2003PNAS..10014036D .
  9. Son J, Du W, Esposito M, Shariati K, Ding H, Kang Y, Accili D . Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure . Nature Communications . 14 . 1 . 558 . February 2023 . 36732513 . 9895451 . 10.1038/s41467-023-36315-4 . 2023NatCo..14..558S .
  10. Li D, Shao NY, Moonen JR, Zhao Z, Shi M, Otsuki S, Wang L, Nguyen T, Yan E, Marciano DP, Contrepois K, Li CG, Wu JC, Snyder MP, Rabinovitch M . ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension . Circulation . 143 . 21 . 2074–2090 . May 2021 . 33764154 . 8289565 . 10.1161/CIRCULATIONAHA.120.048845 .
  11. Xie X, Urabe G, Marcho L, Stratton M, Guo LW, Kent CK . ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation . English . iScience . 19 . 872–882 . September 2019 . 31513972 . 6739626 . 10.1016/j.isci.2019.08.044 . 2019iSci...19..872X .
  12. Devalaraja S, To TK, Folkert IW, Natesan R, Alam MZ, Li M, Tada Y, Budagyan K, Dang MT, Zhai L, Lobel GP, Ciotti GE, Eisinger-Mathason TS, Asangani IA, Weber K, Simon MC, Haldar M . Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression . English . Cell . 180 . 6 . 1098–1114.e16 . March 2020 . 32169218 . 7194250 . 10.1016/j.cell.2020.02.042 .
  13. Topping T, Griswold MD . Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis . Frontiers in Endocrinology . 13 . 871225 . 2022 . 35574006 . 9097449 . 10.3389/fendo.2022.871225 . free .
  14. Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, Marselli L, Suleiman M, Ratner LE, Marchetti P, Accili D . Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes . The Journal of Clinical Endocrinology and Metabolism . 101 . 3 . 1044–1054 . March 2016 . 26713822 . 4803182 . 10.1210/jc.2015-2860 .
  15. Kim-Muller JY, Fan J, Kim YJ, Lee SA, Ishida E, Blaner WS, Accili D . Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice . Nature Communications . 7 . 1 . 12631 . August 2016 . 27572106 . 5013715 . 10.1038/ncomms12631 . 2016NatCo...712631K .
  16. Shimamura M, Karasawa H, Sakakibara S, Shinagawa A . Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets . Biochemical and Biophysical Research Communications . 401 . 1 . 79–84 . October 2010 . 20833146 . 10.1016/j.bbrc.2010.09.013 .
  17. Kim-Muller JY, Fan J, Kim YJ, Lee SA, Ishida E, Blaner WS, Accili D . Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice . Nature Communications . 7 . 1 . 12631 . August 2016 . 27572106 . 5013715 . 10.1038/ncomms12631 . 2016NatCo...712631K .
  18. Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, Valanis B, Williams JH . The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements . Journal of the National Cancer Institute . 96 . 23 . 1743–1750 . December 2004 . 15572756 . 10.1093/jnci/djh320 .
  19. Luo Y, Dallaglio K, Chen Y, Robinson WA, Robinson SE, McCarter MD, Wang J, Gonzalez R, Thompson DC, Norris DA, Roop DR, Vasiliou V, Fujita M . ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets . Stem Cells . 30 . 10 . 2100–2113 . October 2012 . 22887839 . 3448863 . 10.1002/stem.1193 .
  20. Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, Wang M, Hu B, Cheng SY, Sobol RW, Nakano I . Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3 . Proceedings of the National Academy of Sciences of the United States of America . 110 . 21 . 8644–8649 . May 2013 . 23650391 . 3666732 . 10.1073/pnas.1221478110 . free . 2013PNAS..110.8644M .
  21. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Liu H, Behrens C, Shay JW, Wistuba II, Minna JD . Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway . Clinical Cancer Research . 20 . 15 . 4154–4166 . August 2014 . 24907115 . 4438754 . 10.1158/1078-0432.CCR-13-3292 .
  22. Jia J, Parikh H, Xiao W, Hoskins JW, Pflicke H, Liu X, Collins I, Zhou W, Wang Z, Powell J, Thorgeirsson SS, Rudloff U, Petersen GM, Amundadottir LT . An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer . BMC Medical Genomics . 6 . 1 . 33 . September 2013 . 24053169 . 3849454 . 10.1186/1755-8794-6-33 . free .
  23. Marcato P, Dean CA, Liu RZ, Coyle KM, Bydoun M, Wallace M, Clements D, Turner C, Mathenge EG, Gujar SA, Giacomantonio CA, Mackey JR, Godbout R, Lee PW . Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling . Molecular Oncology . 9 . 1 . 17–31 . January 2015 . 25106087 . 5528683 . 10.1016/j.molonc.2014.07.010 .

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