Retinal dehydrogenase

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retinal dehydrogenase
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retinal dehydrogenase inhibited by Yb
Identifiers
EC no. 1.2.1.36
CAS no. 37250-99-0
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In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on aldehyde or oxo- donor groups with NAD+ or NADP+ as acceptor groups, the systematic name being retinal:NAD+ oxidoreductase. This enzyme participates in retinol metabolism. The general scheme for the reaction catalyzed by this enzyme is:

Contents

retinal + NAD+ + H2O retinoic acid + NADH + H+

Structure

Retinal dehydrogenase is a tetramer of identical units, consisting of a dimer of dimers. [1] Retinal dehydrogenase monomers are composed of three domains: a nucleotide-binding domain, a tetramerization domain, and a catalytic domain. The dimer can be pictured as an "X" with the dimers forming upper and lower halves that cross over each other. Interestingly, the nucleotide-binding domain of retinal dehydrogenase contains 5 instead of the usual 6 β-strands in the Rossman fold. [2] This appears to be conserved across many aldehyde dehydrogenases. The tetramerization domains lie equatorially along the "X" and the nucleotide binding regions appear on the tips of the "X". Nearby the tetramerization domain lies a 12 Å deep tunnel that gives the substrate access to the key catalytic regions. [1] Residues near the C-terminal end of the catalytic domain have been found to impart specificity in other aldehyde dehydrogenases. Common to many aldehyde dehydrogenases is a catalytic cysteine, which was found to be present in RALDH2, a specific retinal dehydrogenase for which the structure has been solved. [1] [3] [4]

A depiction of the Rossman fold in retinal dehydrogenase (PDB 1BI9) highlighting the unique 5 b-strands instead of the traditional 6. NAD shown in pink for clarity. Retinal Dehydrogenase Rossman Fold.png
A depiction of the Rossman fold in retinal dehydrogenase (PDB 1BI9) highlighting the unique 5 β-strands instead of the traditional 6. NAD shown in pink for clarity.

Specificity

There are three general classes of aldehyde dehydrogenases: class 1 (ALDH1) comprises cytosolic proteins, class 2 (ALDH2) includes mitochondrial proteins, and class 3 (ALDH3) includes tumor-related proteins. [4] ALDH1 enzymes show a high specificity for all-trans retinal and 9-cis retinal in kinetic studies of sheep liver aldehyde dehydrogenases while ALDH2 enzymes show little affinity for retinal and instead appears to be mainly involved in the oxidation of acetaldehyde. [5] [6] The entrance tunnel to the enzyme active site appears to provide the specificity observed in ALDH1 for retinal as a substrate. The size of the tunnel is key in imparting this specificity: the solvent-accessible diameter of the entrance tunnel is 150 Å3 in ALDH1, so the relatively large retinal can be accommodated while the solvent accessible diameter in ALDH2 is only 20 Å3 which limits accessibility to retinal but amply accommodates acetaldehyde. [7]

Mechanism

The proposed mechanism of retinal dehydrogenase begins with a key cysteine residue in the active site attacking the aldehyde group in retinal to form a thiohemiacetal intermediate. [3] Then, a hydride shift is facilitated by the enzyme to form NADH and a thioester intermediate. This hydride shift has been shown to be stereospecific in a subset (class 3) of retinal dehydrogenases. [8] The thioester intermediate is then attacked by a water molecule, which is made more nucleophilic by a glutamate residue that lies near the active site. [9] There has been some debate as to whether the glutamate residue near the active site acts as a general base during the reaction or whether it is more limited and merely deprotonates the catalytic cysteine to make the cysteine more nucleophilic. [9] Kinetic studies have supported this mechanism by showing that the reaction follows an ordered sequential path with NAD+ binding first which is followed by the binding of retinal, the catalytic breakdown of retinal to retinoic acid, the release of retinoic acid, and finally the release of NADH. [10]

The mechanism of retinal dehydrogenase. NAD and protein side chains shown in red for clarity. Retinal Dehydrogenase Mechanism.png
The mechanism of retinal dehydrogenase. NAD and protein side chains shown in red for clarity.

Regulation

Some of the strategies for regulating retinal dehydrogenases are only now becoming more clear after in vivo regulation remained mysterious for some time, though much of the current research on regulation has focused on the modulation of gene expression rather than direct protein regulation. [7] Dendritic cells in the gut help in modulating immune tolerance through the activity of retinal dehydrogenase; expression in these cells may be driven by a TNF receptor, 4-1-BB. [11] It was also shown that the expression of a certain retinal dehydrogenase found in humans, retinal short-chain dehydrogenase/reductase (retSDR1), is increased by tumor-suppressor proteins p53 and p63, suggesting that retSDR1 may have tumor-preventing activities. [12] Expression of retinal dehydrogenase types 1 and 2 genes is enhanced by the addition of cholesterol or cholesterol derivatives. [13] Disulfiram is a drug used to artificially regulate aldehyde dehydrogenase activity in patients with alcoholism by inhibiting the activity of aldehyde dehydrogenases, though it is not specific to retinal dehydrogenase. [14] Other exogenous molecules have also been found to inhibit retinal dehydrogenase activity including nitrofen, 4-biphenyl carboxylic acid, bisdiamine, and SB-210661. [15]

Clinical significance

Retinal dehydrogenase plays a key role in the biosynthesis of retinoic acid, which in turn acts in cell signaling pathways. Retinoic acid is distinct from other cell signaling molecules in that it diffuses into the nucleus and binds directly to gene targets via retinoic acid receptors. [16] This retinoic acid signaling pathway also appears to be unique to chordates, as suggested by the presence of retinal dehydrogenases exclusively in chordates. [17] Retinoic acid signaling appears to control developmental processes like neurogenesis, cardiogenesis, forelimb bud development, foregut development, and eye development. Retinoic acid signaling is also important for maintaining adult neuronal and epithelium cell type. [18] Retinoic acid is generated in organisms by first oxidizing retinol (Vitamin A) to retinal with an alcohol dehydrogenase. Then, a retinal dehydrogenase oxidizes retinal to retinoic acid. The production of retinoic acid from vitamin A must be tightly controlled as high levels of retinoic acid and vitamin A can lead to toxic effects, while vitamin A deficiency leads to its own issues in development. [19] [20] This provides a rationale for many of the transcriptional regulatory strategies discussed earlier. In humans, mutations in a gene coding for a certain retinal dehydrogenase (RDH12) can also lead to Leber's congenital amaurosis, a retinal dystrophy responsible for many cases of congenital blindness. [21]

Isoforms

Different isoforms of retinal dehydrogenase exist and play a key role in development, as the types are differentially expressed inside a developing embryo. The enzyme retinal dehydrogenase type-2 (RALDH2) catalyzes much of the retinoic acid formation during development, but not all. RALDH2 is crucial for development midgestation and helps drive neural, heart, lung, and forelimb development; it is also responsible for all retinoic acid development during certain periods of midgestation. [22] Later in development, retinal dehydrogenase type-1 (RALDH1) begins activity in the dorsal pit of the retina and retinal dehydrogenase type-3 (RALDH3) becomes active in the olfactory pit, ventral retina, and urinary tract. Raldh2 gene knockouts are fatal in mice during development since the brain cannot develop normally. [23] Raldh3 gene knockout is fatal at birth in mice since nasal passages are not properly developed and instead are blocked. [24] Raldh1 knockouts are not fatal and, interestingly, have been shown to be protective against diet-induced obesity in mice in a retinoid-independent manner. [25]

Related Research Articles

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin and an essential nutrient for animals. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinal, retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Retinol</span> Chemical compound

Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.

<span class="mw-page-title-main">Alcohol dehydrogenase</span> Group of dehydrogenase enzymes

Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that are otherwise toxic, and they also participate in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.

<span class="mw-page-title-main">Acetaldehyde dehydrogenase</span> Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

<span class="mw-page-title-main">Pyruvate dehydrogenase complex</span> Three-enzyme complex responsible for pyruvate decarboxylation

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Malate dehydrogenase</span> Class of enzymes

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acetyl-CoA. Once acetyl-CoA is formed, it becomes a substrate for the citric acid cycle ultimately producing cellular energy and releasing water and carbon dioxide. Due to differences in enzyme presence and availability, human adults and fetuses process ethanol through different pathways. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. The liver is the major organ that metabolizes ethanol due to its high concentration of these enzymes.

<span class="mw-page-title-main">Long-chain-aldehyde dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Fatty aldehyde dehydrogenase is an aldehyde dehydrogenase enzyme that in human is encoded in the ALDH3A2 gene on chromosome 17. Aldehyde dehydrogenase enzymes function to remove toxic aldehydes that are generated by the metabolism of alcohol and by lipid peroxidation.

<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations.

<span class="mw-page-title-main">Serine dehydratase</span>

Serine dehydratase or L-serine ammonia lyase (SDH) is in the β-family of pyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structural and properties vary among species. SDH is found in yeast, bacteria, and the cytoplasm of mammalian hepatocytes. SDH catalyzes is the deamination of L-serine to yield pyruvate, with the release of ammonia.

In enzymology, a retinol dehydrogenase (RDH) (EC 1.1.1.105) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Formaldehyde dehydrogenase</span>

In enzymology, a formaldehyde dehydrogenase (EC 1.2.1.46) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">ADH1B</span> Protein-coding gene in the species Homo sapiens

Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.

<span class="mw-page-title-main">Aldehyde dehydrogenase 3 family, member A1</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.

<span class="mw-page-title-main">ALDH1A2</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.

<span class="mw-page-title-main">Inosine-5′-monophosphate dehydrogenase</span> Class of enzymes

Inosine-5′-monophosphate dehydrogenase (IMPDH) is a purine biosynthetic enzyme that catalyzes the nicotinamide adenine dinucleotide (NAD+)-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first committed and rate-limiting step towards the de novo biosynthesis of guanine nucleotides from IMP. IMPDH is a regulator of the intracellular guanine nucleotide pool, and is therefore important for DNA and RNA synthesis, signal transduction, energy transfer, glycoprotein synthesis, as well as other process that are involved in cellular proliferation.

References

  1. 1 2 3 Lamb AL, Newcomer ME (May 1999). "The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity". Biochemistry. 38 (19): 6003–11. doi:10.1021/bi9900471. PMID   10320326.
  2. 1 2 Liu ZJ, Sun YJ, Rose J, Chung YJ, Hsiao CD, Chang WR, Kuo I, Perozich J, Lindahl R, Hempel J, Wang BC (April 1997). "The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold". Nature Structural Biology. 4 (4): 317–26. doi:10.1038/nsb0497-317. PMID   9095201. S2CID   21436007.
  3. 1 2 3 Abriola DP, Fields R, Stein S, MacKerell AD, Pietruszko R (September 1987). "Active site of human liver aldehyde dehydrogenase". Biochemistry. 26 (18): 5679–84. doi:10.1021/bi00392a015. PMID   3676276.
  4. 1 2 Farrés J, Wang TT, Cunningham SJ, Weiner H (February 1995). "Investigation of the active site cysteine residue of rat liver mitochondrial aldehyde dehydrogenase by site-directed mutagenesis". Biochemistry. 34 (8): 2592–8. doi:10.1021/bi00008a025. PMID   7873540.
  5. ↑ Yoshida A, Hsu LC, Davé V (1992). "Retinal oxidation activity and biological role of human cytosolic aldehyde dehydrogenase". Enzyme. 46 (4–5): 239–44. doi:10.1159/000468794. PMID   1292933.
  6. ↑ Kitson KE, Blythe TJ (1999). "The hunt for a retinal-specific aldehyde dehydrogenase in sheep liver". Advances in Experimental Medicine and Biology. 463: 213–21. doi:10.1007/978-1-4615-4735-8_26. ISBN   978-1-4613-7146-5. PMID   10352688.
  7. 1 2 Moore SA, Baker HM, Blythe TJ, Kitson KE, Kitson TM, Baker EN (December 1998). "Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases". Structure. 6 (12): 1541–51. doi: 10.1016/S0969-2126(98)00152-X . PMID   9862807.
  8. ↑ Jones KH, Lindahl R, Baker DC, Timkovich R (August 1987). "Hydride transfer stereospecificity of rat liver aldehyde dehydrogenases". The Journal of Biological Chemistry. 262 (23): 10911–3. doi: 10.1016/S0021-9258(18)60901-9 . PMID   3038902.
  9. 1 2 Wang X, Weiner H (January 1995). "Involvement of glutamate 268 in the active site of human liver mitochondrial (class 2) aldehyde dehydrogenase as probed by site-directed mutagenesis". Biochemistry. 34 (1): 237–43. doi:10.1021/bi00001a028. PMID   7819202.
  10. ↑ Hart GJ, Dickinson FM (June 1982). "Kinetic properties of highly purified preparations of sheep liver cytoplasmic aldehyde dehydrogenase". The Biochemical Journal. 203 (3): 617–27. doi:10.1042/bj2030617. PMC   1158276 . PMID   7115304.
  11. ↑ Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, Croft M (September 2012). "Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase". Journal of Immunology. 189 (6): 2697–701. doi:10.4049/jimmunol.1201248. PMC   3436963 . PMID   22896640.
  12. ↑ Kirschner RD, Rother K, Müller GA, Engeland K (June 2010). "The retinal dehydrogenase/reductase retSDR1/DHRS3 gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes". Cell Cycle. 9 (11): 2177–88. doi: 10.4161/cc.9.11.11844 . PMID   20543567.
  13. ↑ Huq MD, Tsai NP, Gupta P, Wei LN (July 2006). "Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites". The EMBO Journal. 25 (13): 3203–13. doi:10.1038/sj.emboj.7601181. PMC   1500992 . PMID   16763553.
  14. ↑ Lipsky JJ, Berti JJ, Aquilina JW, Mays DC (October 1997). "Effect of a disulfiram metabolite on retinaldehyde metabolism". Lancet. 350 (9085): 1176. doi: 10.1016/S0140-6736(05)63821-4 . PMID   9343525. S2CID   29898775.
  15. ↑ Mey J, Babiuk RP, Clugston R, Zhang W, Greer JJ (February 2003). "Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents". The American Journal of Pathology. 162 (2): 673–9. doi:10.1016/S0002-9440(10)63861-8. PMC   1851155 . PMID   12547725.
  16. ↑ Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ (November 2001). "Nuclear receptors and lipid physiology: opening the X-files". Science. 294 (5548): 1866–70. Bibcode:2001Sci...294.1866C. doi:10.1126/science.294.5548.1866. PMID   11729302.
  17. ↑ Marlétaz F, Holland LZ, Laudet V, Schubert M (2006). "Retinoic acid signaling and the evolution of chordates". International Journal of Biological Sciences. 2 (2): 38–47. doi:10.7150/ijbs.2.38. PMC   1458431 . PMID   16733532.
  18. ↑ Maden M (October 2007). "Retinoic acid in the development, regeneration and maintenance of the nervous system". Nature Reviews. Neuroscience. 8 (10): 755–65. doi:10.1038/nrn2212. PMID   17882253. S2CID   13581692.
  19. ↑ Guillonneau M, Jacqz-Aigrain E (September 1997). "[Teratogenic effects of vitamin A and its derivates]". Archives de Pédiatrie. 4 (9): 867–74. doi:10.1016/S0929-693X(97)88158-4. PMID   9345570.
  20. ↑ Dickman ED, Thaller C, Smith SM (August 1997). "Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects". Development. 124 (16): 3111–21. doi:10.1242/dev.124.16.3111. PMID   9272952.
  21. ↑ Perrault I, Hanein S, Gerber S, Barbet F, Ducroq D, Dollfus H, Hamel C, Dufier JL, Munnich A, Kaplan J, Rozet JM (October 2004). "Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis". American Journal of Human Genetics. 75 (4): 639–46. doi:10.1086/424889. PMC   1182050 . PMID   15322982.
  22. ↑ Molotkova N, Molotkov A, Sirbu IO, Duester G (February 2005). "Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation". Mechanisms of Development. 122 (2): 145–55. doi:10.1016/j.mod.2004.10.008. PMC   2826194 . PMID   15652703.
  23. ↑ Mic FA, Haselbeck RJ, Cuenca AE, Duester G (May 2002). "Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice". Development. 129 (9): 2271–82. doi:10.1242/dev.129.9.2271. PMC   2833017 . PMID   11959834.
  24. ↑ Molotkov A, Molotkova N, Duester G (May 2006). "Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning". Development. 133 (10): 1901–10. doi:10.1242/dev.02328. PMC   2833011 . PMID   16611695.
  25. ↑ Yang D, Krois CR, Huang P, Wang J, Min J, Yoo HS, Deng Y, Napoli JL (November 2, 2017). "Raldh1 promotes adiposity during adolescence independently of retinal signaling". PLOS ONE. 12 (11): e0187669. Bibcode:2017PLoSO..1287669Y. doi: 10.1371/journal.pone.0187669 . PMC   5667840 . PMID   29095919.
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