Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. The hALDH Protein Superfamily: Structure Description, Comparison, and Classification
3. The Multiple Physiological Roles of hALDHs
3.1. hALDHs Are Active Enzymes
3.1.1. Aldehyde Dehydrogenases
3.1.2. Esterases
3.1.3. Nitrate Reductases
3.2. ALDHs Are Pseudoenzymes
3.3. ALDHs Are Molecular Chaperones
3.3.1. Crystallins and Anti-Stress Protein Factors
3.3.2. Osmotic Pressure Regulators
3.4. ALDHs Are Binding Scaffolds
4. hALDHs Are Associated with Chronic Diseases and Conditions
5. hALDHs Are Key Players in Cancer Pathology
6. The Role of hALDH Proteins in Resistance to Chemotherapies
7. Cancer Therapeutic Treatments Based on hALDH Inhibition
7.1. Non-Specific hALDH Inhibitors
7.2. Specific hALDH Inhibitors
7.2.1. ALDH1A1 Specific Inhibitors
7.2.2. ALDH1A3 Specific Inhibitors
7.2.3. ALDH1B1 Specific Inhibitors
7.2.4. ALDH1Ai Specific Inhibitors
7.2.5. ALDH2 Specific Inhibitors
7.2.6. ALDH3A1 Specific Inhibitors
7.2.7. ALDH4A1 Specific Inhibitors
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Family | Gene/Protein | Tissue/Organ Distribution | Subcellular Localization | Quaternary Structure | Major Substrate | Representative PDBs |
1. ALDH1/2 | Aldh1a1/ Retinal Dehydrogenase 1 | Liver, duodenum, stomach, small intestine, erythrocytes, skeletal muscle, lung, breast, other | Cytosol | Tetramer | Retinal | 4WJ9, 4WB9, 4WPN |
Aldh1a2/ Retinal Dehydrogenase 2 | Testis, endometrium, prostate, ovary, other | Cytosol | Tetramer | Retinal | 4X2Q, 6B5H | |
Aldh1a3/ Retinal Dehydrogenase 3 | Prostate, bladder, testis, kidney, other | Cytosol | Tetramer | Retinal | 5FHZ, 6TGW, 7A6Q | |
Aldh1b1/ALDHx or ALDH5 or ALDH1B1 | Liver, kidney, heart, lung, stomach, other | Mitochondrion | Tetramer | Acetaldehyde | 7MJD, 7RAD, 7MJC | |
Aldh2/ALDH2 | Liver, kidney, heart, skeletal muscle, lung, other | Mitochondrion | Tetramer | Acetaldehyde | 1O05, 1ZUM (ALDH2*2) | |
Aldh1l1/FDH or cytosolic 10-formyltetrahydrofolate dehydrogenase or 10-FTHFDH | Liver, kidneys, brain, urinary bladder, skeletal muscle, testis, other | Cytosol | Tetramer | Folate | 2BW0 (Hydrolase domain) | |
Aldh1l2/mtFDH or mitochondrial 10-formyltetrahydrofolate dehydrogenase | Pancreas, brain, stomach, thyroid gland, salivary gland, other | Mitochondrion | Tetramer | Folate | ||
2. ALDH3 | Aldh3a1/ALDH3A1 | Stomach, skin, cornea, esophagus, other | Cytosol | Dimer | Aromatic aldehydes | 3SZA, 4L2O |
Aldh3a2/Fatty ALDH | Skin, heart, lung, adrenal glands, kidney, liver, other | Microsome/ ER membrane | Dimer | Fatty aldehydes | 4QGK | |
Aldh3b1/ALDH3B1 | Liver, lung, kidney, stomach, breast, other | Cytosol Cell membrane | Unknown | Medium/Long chain aldehydes | ||
Aldh3b2/ALDH3B2 | Skin, esophagus, breast, other | Lipid droplet | Unknown | Medium/Long chain aldehydes | ||
3. ALDH4 | Aldh4a1/P5CDH or Delta-1-pyrroline-5-carboxylate dehydrogenase | Liver, kidney, heart, lung, brain, other | Mitochondrion | Dimer | Glutamate γ-semialdehyde | 3V9G |
4. ALDH5 | Aldh5a1/SSADH or Succinate-semialdehyde dehydrogenase | Liver, kidney, testis, stomach, heart, brain, other | Mitochondrion | Tetramer (12mer/reduced form) | Succinic semialdehyde | 2W8N (oxidized), 2W8O (reduced) |
5. ALDH6 | Aldh6a1/MMSDH or Methylmalonate-semialdehyde dehydrogenase | Liver, kidney, brain, stomach, heart, other | Mitochondrion | Tetramer | Methylmalonate semialdehyde | |
6. ALDH7 | Aldh7a1/AASADH or Alpha-aminoadipic semialdehyde dehydrogenase | Liver, kidney, heart, brain, lung, stomach, other | Cytosol/Nucleus | Tetramer | Betaine aldehyde | 2J6L, 4ZUL, 4ZUK |
7. ALDH8 | Aldh8a1/ALDH8A1 or 2-aminomuconic semialdehyde dehydrogenase | Liver, kidney, brain, breast, other | Cytosol | Unknown | Retinal | |
8. ALDH9 | Aldh9a1/ALDH9A1 or TMABA-DH or 4-trimethylaminobutyraldehyde dehydrogenase | Thyroid gland, brain, liver, breast, testis, other | Cytosol | Tetramer | γ-aminobutyraldehyde | 6QAK, 6QAO, 6QAP, 6VR6 |
9. ALDH16 | Aldh16a1/ALDH16A1 | Spleen, duodenum, stomach, kidney, other | Cell membrane | Unknown | Unknown | |
10. ALDH18 | Aldh18a1/ALDH18A1 or P5C Synthetase or Delta-1-pyrroline-5-carboxylate synthase | Small intestine, duodenum, colon, testis, salivary gland, other | Mitochondrion Inner Membrane | Dimer | Glutamatic γ-semi aldehyde | 2H5G |
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Xanthis, V.; Mantso, T.; Dimtsi, A.; Pappa, A.; Fadouloglou, V.E. Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer. Cancers 2023, 15, 4419. https://doi.org/10.3390/cancers15174419
Xanthis V, Mantso T, Dimtsi A, Pappa A, Fadouloglou VE. Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer. Cancers. 2023; 15(17):4419. https://doi.org/10.3390/cancers15174419
Chicago/Turabian StyleXanthis, Vasileios, Theodora Mantso, Anna Dimtsi, Aglaia Pappa, and Vasiliki E. Fadouloglou. 2023. "Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer" Cancers 15, no. 17: 4419. https://doi.org/10.3390/cancers15174419