Biology:ALDH1A3

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[3] 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[4] or healthy adult humans.[7] ALDH1a3 is a potential therapeutic target in type 2 diabetes.[8] cardiovascular disorders,[9][10] and cancer[11] where its expression is amplified and it has known pathogenic activity.[2] ALDH1a3 is not necessary for spermatogenesis[12] or the visual cycle.[2]

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[13] and mouse models of diabetes.[14] ALDH1a3 expression has been shown to suppress insulin secretion and increase glucagon production in laboratory experiments.[15] 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.[8][14]

Cardiovascular Disorders

ALDH1a3 is activated in injured or inflamed vascular smooth muscle cells in the context of pulmonary arterial hypertension[9] and neointimal hyperplasia.[10] 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.[16]

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,[17] glioblastoma,[18] lung cancer,[19] pancreatic cancer,[20] breast cancer,[21] sarcomas[11] and many other cancer types.[2] 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.[11]

References

  1. ↑ "Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6". Genomics 24 (2): 333–341. November 1994. doi:10.1006/geno.1994.1624. PMID 7698756. 
  2. ↑ 2.0 2.1 2.2 2.3 "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine 221 (9). September 2024. doi:10.1084/jem.20240519. PMID 39133222. 
  3. ↑ 3.0 3.1 "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. doi:10.1124/pr.111.005538. PMID 22544865. 
  4. ↑ 4.0 4.1 "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. doi:10.1073/pnas.2336223100. PMID 14623956. Bibcode: 2003PNAS..10014036D. 
  5. ↑ "Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid". Scientific Reports 6 (1). October 2016. doi:10.1038/srep35710. PMID 27759097. Bibcode: 2016NatSR...635710M. 
  6. ↑ "Tissue expression of ALDH1A3 - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000184254-ALDH1A3/tissue. 
  7. ↑ 7.0 7.1 "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. doi:10.1016/0041-008X(61)90002-3. PMID 13713106. Bibcode: 1961ToxAP...3....1H. 
  8. ↑ 8.0 8.1 "Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure". Nature Communications 14 (1). February 2023. doi:10.1038/s41467-023-36315-4. PMID 36732513. Bibcode: 2023NatCo..14..558S. 
  9. ↑ 9.0 9.1 "ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension". Circulation 143 (21): 2074–2090. May 2021. doi:10.1161/CIRCULATIONAHA.120.048845. PMID 33764154. 
  10. ↑ 10.0 10.1 "ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation" (in English). iScience 19: 872–882. September 2019. doi:10.1016/j.isci.2019.08.044. PMID 31513972. Bibcode: 2019iSci...19..872X. 
  11. ↑ 11.0 11.1 11.2 "Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression" (in English). Cell 180 (6): 1098–1114.e16. March 2020. doi:10.1016/j.cell.2020.02.042. PMID 32169218. 
  12. ↑ "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology 13. 2022. doi:10.3389/fendo.2022.871225. PMID 35574006. 
  13. ↑ "Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes". The Journal of Clinical Endocrinology and Metabolism 101 (3): 1044–1054. March 2016. doi:10.1210/jc.2015-2860. PMID 26713822. 
  14. ↑ 14.0 14.1 "Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice". Nature Communications 7 (1). August 2016. doi:10.1038/ncomms12631. PMID 27572106. Bibcode: 2016NatCo...712631K. 
  15. ↑ "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. doi:10.1016/j.bbrc.2010.09.013. PMID 20833146. Bibcode: 2010BBRC..401...79S. 
  16. ↑ "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. doi:10.1093/jnci/djh320. PMID 15572756. 
  17. ↑ "ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets". Stem Cells 30 (10): 2100–2113. October 2012. doi:10.1002/stem.1193. PMID 22887839. 
  18. ↑ "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. doi:10.1073/pnas.1221478110. PMID 23650391. Bibcode: 2013PNAS..110.8644M. 
  19. ↑ "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. doi:10.1158/1078-0432.CCR-13-3292. PMID 24907115. 
  20. ↑ "An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer". BMC Medical Genomics 6 (1). September 2013. doi:10.1186/1755-8794-6-33. PMID 24053169. 
  21. ↑ "Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling". Molecular Oncology 9 (1): 17–31. January 2015. doi:10.1016/j.molonc.2014.07.010. PMID 25106087. 

Further reading

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




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