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ALDH1A3

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ALDH1A3
Identifiers
AliasesALDH1A3, ALDH1A6, ALDH6, MCOP8, RALDH3, aldehyde dehydrogenase 1 family member A3
External IDsOMIM: 600463; MGI: 1861722; HomoloGene: 68080; GeneCards: ALDH1A3; OMA:ALDH1A3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

220

56847

Ensembl

ENSG00000184254

ENSMUSG00000015134

UniProt

P47895

Q9JHW9

RefSeq (mRNA)

NM_001293815
NM_000693
NM_001037224

NM_053080

RefSeq (protein)

NP_000684
NP_001280744

NP_444310

Location (UCSC)Chr 15: 100.88 – 100.92 MbChr 7: 66.04 – 66.08 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.,[5]

Function

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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.[6] While ALDH1a3 and related isozymes are known to utilize many aldehyde substrates in biochemical experiments,[7] genetic and functional analysis demonstrates that ALDH1a3 functions only to oxidize all-trans retinaldehyde in living systems.[8] ALDH1a3 exists as a homotetramer[9] with cytosolic localization. It is not known to have any function in healthy adult tissues.[10] ALDH1a3 contains a catalytic cysteine residue which is only minimally inhibited by the ALDH2-targeted drug disulfiram.[7] 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.[11]

The function of ALDH1a3 is known to be restricted to early fetal development and is dispensable in either adult mammals[12] or healthy adult humans.[11] ALDH1a3 is a potential therapeutic target in type 2 diabetes.[13] cardiovascular disorders,[14][15] and cancer[16] where its expression is amplified and it has known pathogenic activity.[6] ALDH1a3 is not necessary for spermatogenesis[17] or the visual cycle.[6]

Clinical significance

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Type 2 Diabetes

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ALDH1a3 is established as a primary marker of failing beta cells in the pancreas, both in human type 2 diabetes patients[18] and mouse models of diabetes.[19] ALDH1a3 expression has been shown to suppress insulin secretion and increase glucagon production in laboratory experiments.[20] 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.[13][21]

Cardiovascular Disorders

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ALDH1a3 is activated in injured or inflamed vascular smooth muscle cells in the context of pulmonary arterial hypertension[14] and neointimal hyperplasia.[15] 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.[22]

Cancer

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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,[23] glioblastoma,[24] lung cancer,[25] pancreatic cancer,[26] breast cancer,[27] sarcomas[16] and many other cancer types.[6] 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.[16]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000184254 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015134 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Hsu LC, Chang WC, Hiraoka L, Hsieh CL (November 1994). "Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6". Genomics. 24 (2): 333–341. doi:10.1006/geno.1994.1624. PMID 7698756.
  6. ^ a b c d Esposito M, Amory JK, Kang Y (September 2024). "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine. 221 (9): e20240519. doi:10.1084/jem.20240519. PMC 11318670. PMID 39133222.
  7. ^ a b Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, et al. (July 2012). Sibley DR (ed.). "Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application". Pharmacological Reviews. 64 (3): 520–539. doi:10.1124/pr.111.005538. PMC 3400832. PMID 22544865.
  8. ^ Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB (November 2003). "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. Bibcode:2003PNAS..10014036D. doi:10.1073/pnas.2336223100. PMC 283541. PMID 14623956.
  9. ^ Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S (October 2016). "Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid". Scientific Reports. 6 (1): 35710. doi:10.1038/srep35710. PMC 5069622. PMID 27759097.
  10. ^ "Tissue expression of ALDH1A3 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2024-12-03.
  11. ^ a b Heller CG, Moore DJ, Paulsen CA (January 1961). "Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 3 (1): 1–11. Bibcode:1961ToxAP...3....1H. doi:10.1016/0041-008X(61)90002-3. PMID 13713106.
  12. ^ Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB (November 2003). "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. Bibcode:2003PNAS..10014036D. doi:10.1073/pnas.2336223100. PMC 283541. PMID 14623956.
  13. ^ a b Son J, Du W, Esposito M, Shariati K, Ding H, Kang Y, et al. (February 2023). "Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure". Nature Communications. 14 (1): 558. Bibcode:2023NatCo..14..558S. doi:10.1038/s41467-023-36315-4. PMC 9895451. PMID 36732513.
  14. ^ a b Li D, Shao NY, Moonen JR, Zhao Z, Shi M, Otsuki S, et al. (May 2021). "ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension". Circulation. 143 (21): 2074–2090. doi:10.1161/CIRCULATIONAHA.120.048845. PMC 8289565. PMID 33764154.
  15. ^ a b Xie X, Urabe G, Marcho L, Stratton M, Guo LW, Kent CK (September 2019). "ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation". iScience. 19: 872–882. Bibcode:2019iSci...19..872X. doi:10.1016/j.isci.2019.08.044. PMC 6739626. PMID 31513972.
  16. ^ a b c Devalaraja S, To TK, Folkert IW, Natesan R, Alam MZ, Li M, et al. (March 2020). "Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression". Cell. 180 (6): 1098–1114.e16. doi:10.1016/j.cell.2020.02.042. PMC 7194250. PMID 32169218.
  17. ^ Topping T, Griswold MD (2022). "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology. 13: 871225. doi:10.3389/fendo.2022.871225. PMC 9097449. PMID 35574006.
  18. ^ Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. (March 2016). "Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes". The Journal of Clinical Endocrinology and Metabolism. 101 (3): 1044–1054. doi:10.1210/jc.2015-2860. PMC 4803182. PMID 26713822.
  19. ^ Kim-Muller JY, Fan J, Kim YJ, Lee SA, Ishida E, Blaner WS, et al. (August 2016). "Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice". Nature Communications. 7 (1): 12631. Bibcode:2016NatCo...712631K. doi:10.1038/ncomms12631. PMC 5013715. PMID 27572106.
  20. ^ Shimamura M, Karasawa H, Sakakibara S, Shinagawa A (October 2010). "Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets". Biochemical and Biophysical Research Communications. 401 (1): 79–84. doi:10.1016/j.bbrc.2010.09.013. PMID 20833146.
  21. ^ Kim-Muller JY, Fan J, Kim YJ, Lee SA, Ishida E, Blaner WS, et al. (August 2016). "Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice". Nature Communications. 7 (1): 12631. Bibcode:2016NatCo...712631K. doi:10.1038/ncomms12631. PMC 5013715. PMID 27572106.
  22. ^ Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, et al. (December 2004). "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. doi:10.1093/jnci/djh320. PMID 15572756.
  23. ^ Luo Y, Dallaglio K, Chen Y, Robinson WA, Robinson SE, McCarter MD, et al. (October 2012). "ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets". Stem Cells. 30 (10): 2100–2113. doi:10.1002/stem.1193. PMC 3448863. PMID 22887839.
  24. ^ Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. (May 2013). "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. Bibcode:2013PNAS..110.8644M. doi:10.1073/pnas.1221478110. PMC 3666732. PMID 23650391.
  25. ^ Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, et al. (August 2014). "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. doi:10.1158/1078-0432.CCR-13-3292. PMC 4438754. PMID 24907115.
  26. ^ Jia J, Parikh H, Xiao W, Hoskins JW, Pflicke H, Liu X, et al. (September 2013). "An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer". BMC Medical Genomics. 6 (1): 33. doi:10.1186/1755-8794-6-33. PMC 3849454. PMID 24053169.
  27. ^ Marcato P, Dean CA, Liu RZ, Coyle KM, Bydoun M, Wallace M, et al. (January 2015). "Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling". Molecular Oncology. 9 (1): 17–31. doi:10.1016/j.molonc.2014.07.010. PMC 5528683. PMID 25106087.

Further reading

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


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