Pathway Map Details

Retinol metabolism

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3,1.1.21,,, BCDP, (11Z)-Retinal,,, 4-Hydroxy-retinoic acid O4-beta-D- glucuronoside, ADHFE1, 4-Oxoretinoic acid,, ALD9A1, CYP2C19, DHA2, CRABP1, 1.13.11.-, 11-cis-Retinyl palmitate, CYP2C18, CYP3A7, 4-Hydroxy-retinol,,, ALDH2,, Retinoic acid, RDH5, RDH14, Retinol palmitate,,,, 4-Hydroxy-retinoic acid O1-beta-D- glucuronoside, CYP2B6,, CYP2A6, Xanthine oxidase, CYP1B1, CYP2C9, Retinol, DHA6, CYP2C8, DHRS4, RDH12, DHRS3, 4-Hydroxyretinoic acid, CYP2D6, CYP1A2,, UGT1A3,,, UGT1A8, Rhodopsin, RPE65,,, CRABP1, CYP1A1, rhodopsin,,, CYP3A5, CYP3A4, (11Z)-Retinol,, Retinal, AL1A7, CYP4A11,, BCDO, RDH11, beta-Apo-10'-carotenal, beta-Carotene, CYP2E1, UGT2B7, beta-Ionone, AL1A1, 3,1.1.21,


Retinol metabolism

Key enzymes involved in retinoid metabolisms are alcohol and aldehyde dehydrogenases that convert retinols to aldehydes and aldehydes to carboxylic acids, respectively. The first oxidation reaction is catalyzed by a large number of enzymes from the Dehydrogenase/reductase (SDR family), and by classic medium chain Alcohol dehydrogenases [1].

Rhodopsin is converted by photoabsorption to metarhodopsin, and the latter is reconverted to Rhodopsin by light. It is well known that Rhodopsin can be formed from opsin only when (11Z)-Retinal is present. The photoisomerization of Retinal released during the degradation of metarhodopsin is catalyzed by an unknown isomerase is and this photoisomerization stereospecifically directed toward the formation of (11Z)-Retinal [2], [3]. Retinal is also reduced in the reaction catalyzed by all -trans -retinal-specific Retinol dehydrogenases.- Retinol dehydrogenase 11 (all-trans/9-cis/11-cis) ( RDH11 ), [1], [4], Alcohol dehydrogenase, iron containing, 1 (ADHFE1 ), [5], Dehydrogenase/reductase (SDR family) member 3 ( DHRS3 ) [6], Retinol dehydrogenase 5 (11-cis/9-cis) ( RDH5 ) [7], [8], [9], [10], [11], Retinol dehydrogenase 12 (all-trans/9-cis/11-cis) ( RDH12 ) [12], [13], [14], retinol dehydrogenase 14 (all-trans/9-cis/11-cis) ( RDH14 ) [1], [15], dehydrogenase/reductase (SDR family) member (RDH14) [16]. This dehydrogenase activity utilizes [H+] of NADH and does not require NAD + to generate Retinol. These enzymes also catalyze oxidizing (11Z)-Retinol with concomitant generation of [H] NADH to complete the cycle.

Retinol is further isomerized via inversion of the C15 prochiral methylene hydroxyl group configuration resulting in formation of (11Z)-Retinol. This reaction is catalyzed by specific isomerase [17], [18].

Retinol can also esterification to format Retinol palmitate and 11-cis-Retinyl palmitate which can be either stored in the cell or processed further [19]. The 11-cis-Retinyl palmitate can be hydrolyzed at the rate ~20 times faster than Retinol palmitate. Human retinal epithelium contains distinct activities that hydrolyze 11-cis-Retinyl palmitate and Retinol palmitate [20], [21], [19].

Retinal in turn is rapidly oxidized to Retinoic acid by Xanthine dehydrogenase ( Xanthine oxidase ) [22], [23], Aldehyde dehydrogenase 2 family (mitochondrial) ( ALDH2 ) [24], [25], Aldehyde dehydrogenase 1 family, member A3 ( DHA6 ) [26], [27], Aldehyde dehydrogenase 9 family, member A1 ( ALD9A1 ), [24], Aldehyde dehydrogenase 1 family, member A2 ( DHA2 ) [28], and Aldehyde dehydrogenase family 1, subfamily A7 ( AL1A7 ) [29], Aldehyde dehydrogenase 1 family, member A1 ( AL1A1 ) [30], [31]. Retinoic acid is metabolized to 4-Hydroxy-retinoic acid, 4-Oxo-retinoic acid and 5,6-Epoxy-retinoic acid . Oxidation of Retinoic acid to 4-Hydroxy-retinoic acid is catalyzed by cytochrome P-450 isozyme(s) Cytochrome P450, family 2, subfamily C, polypeptides 8, 9, 18, 19 ( CYP2C8, CYP2C9, CYP2C18, CYP2C19 ), Cytochrome P450, family 2, subfamily A, polypeptide 6 ( CYP2A6 ), Cytochrome P450, family 1, subfamily A, polypeptides 1 and 2 ( CYP1A1 and CYP1A2 ), Cytochrome P450, family 3, subfamily A, polypeptides 4, 5 and 7 ( CYP3A4, CYP3A5 and CYP3A7 ), Cytochrome P450, family 2, subfamily S, polypeptide 1 ( CYP2S1 ), Cytochrome P450, family 4, subfamily A, polypeptide 11 ( CYP4A11 ), Cytochrome P450, family 1, subfamily B, polypeptide 1 ( CYP1B1 ), Cytochrome P450, family 2, subfamily B, polypeptide 6 ( CYP2B6 ), Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1 ), Cytochrome P450, family 2, subfamily D, polypeptide 6 ( CYP2D6 ), Cytochrome P450, family 26, subfamily A, polypeptide 1 ( CYP26A1 ) [32], [33], [34], [35], [36], [37]. The next step of Retinoic acid oxidation results in formation of 4-Oxo-retinoic acid and is also catalyzed by P450 cytochromes CYP3A4, CYP1A1, CYP2C9, CYP3A7, CYP2C8, CYP3A5 and CYP4A11 [33], [38].

Glucuronic acid can be conjugated to 4-Hydroxy-retinoic acid, which results in formation of two types of glucuronides: 4-Hydroxy-retinoic acid O1-beta-D-glucuronoside and 4-Hydroxy-retinoic acid O4beta-D-glucuronoside. These reactions are catalyzed by UDP Glucuronosyltransferase 1 family, polypeptide A8 ( UGT1A8 ) [39] and UDP Glucuronosyltransferase 1 family, polypeptide A3 ( UGT1A3 ) [40] to 4-Hydroxy-retinoic acid O1-beta-D-glucuronoside; and by UDP Glucuronosyltransferase 2 family, polypeptide B7 ( UGT2B7 ) [41] and UDP-Glucuronosyltransferase 2 family, member 37 ( UDB5 ) [42] to 4-Hydroxy-retinoic acid O4beta-D-glucuronoside.

Two key enzymes involved in carotenoid metabolism are Beta-carotene 15,15'-monooxygenase 1 ( BCDO ) and Beta-carotene oxygenase 2 ( BCDP ). The first one cleaves Beta-Carotene to form Retinal [43], [44]. The second enzyme is responsible for the unconventional cleavage of Beta-Carotene to form Beta-apo-10'-carotenal and Beta-Ionone [44], [45].


  1. Haeseleer F, Jang GF, Imanishi Y, Driessen CA, Matsumura M, Nelson PS, Palczewski K
    Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. The Journal of biological chemistry 2002 Nov 22;277(47):45537-46
  2. Pepe IM, Cugnoli C
    Retinal photoisomerase: role in invertebrate visual cells. Journal of photochemistry and photobiology. B, Biology. 1992 Apr 15;13(1):5-17
  3. Cugnoli C, Fioravanti R, Pepe IM
    A study on retinal photoisomerization catalyzed by a protein from the honeybee visual system. The Italian journal of biochemistry. 1993 May-Jun;42(3):165-74
  4. Belyaeva OV, Stetsenko AV, Nelson P, Kedishvili NY
    Properties of short-chain dehydrogenase/reductase RalR1: characterization of purified enzyme, its orientation in the microsomal membrane, and distribution in human tissues and cell lines. Biochemistry 2003 Dec 23;42(50):14838-45
  5. Rosell A, Valencia E, Pares X, Fita I, Farres J, Ochoa WF
    Crystal structure of the vertebrate NADP(H)-dependent alcohol dehydrogenase (ADH8). Journal of molecular biology 2003 Jun 27;330(1):75-85
  6. Haeseleer F, Huang J, Lebioda L, Saari JC, Palczewski K
    Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal. The Journal of biological chemistry 1998 Aug 21;273(34):21790-9
  7. Tsigelny I, Baker ME
    Structures important in NAD(P)(H) specificity for mammalian retinol and 11-Cis-retinol dehydrogenases. Biochemical and biophysical research communications 1996 Sep 4;226(1):118-27
  8. Simon A, Lagercrantz J, Bajalica-Lagercrantz S, Eriksson U
    Primary structure of human 11-cis retinol dehydrogenase and organization and chromosomal localization of the corresponding gene. Genomics 1996 Sep 15;36(3):424-30
  9. Wang J, Chai X, Eriksson U, Napoli JL
    Activity of human 11-cis-retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue. The Biochemical journal 1999 Feb 15;338 ( Pt 1):23-7
  10. Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP
    Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nature genetics 1999 Jun;22(2):188-91
  11. Liden M, Romert A, Tryggvason K, Persson B, Eriksson U
    Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus. The Journal of biological chemistry 2001 Dec 28;276(52):49251-7
  12. Belyaeva OV, Korkina OV, Stetsenko AV, Kim T, Nelson PS, Kedishvili NY
    Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids. Biochemistry 2005 May 10;44(18):7035-47
  13. Thompson DA, Janecke AR, Lange J, Feathers KL, Hubner CA, McHenry CL, Stockton DW, Rammesmayer G, Lupski JR, Antinolo G, Ayuso C, Baiget M, Gouras P, Heckenlively JR, den Hollander A, Jacobson SG, Lewis RA, Sieving PA, Wissinger B, Yzer S, Zrenner E, Utermann G, Gal A
    Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Human molecular genetics 2005 Dec 15;14(24):3865-75
  14. Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Schwartz SB, Windsor EA, Roman AJ, Heon E, Stone EM, Thompson DA
    RDH12 and RPE65, visual cycle genes causing leber congenital amaurosis, differ in disease expression. Investigative ophthalmology & visual science 2007 Jan;48(1):332-8
  15. Belyaeva OV, Kedishvili NY
    Human pancreas protein 2 (PAN2) has a retinal reductase activity and is ubiquitously expressed in human tissues. FEBS letters 2002 Nov 20;531(3):489-93
  16. Song MS, Chen W, Zhang M, Napoli JL
    Identification of a mouse short-chain dehydrogenase/reductase gene, retinol dehydrogenase-similar. Function of non-catalytic amino acid residues in enzyme activity. The Journal of biological chemistry 2003 Oct 10;278(41):40079-87
  17. Jin M, Li S, Moghrabi WN, Sun H, Travis GH
    Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 2005 Aug 12;122(3):449-59
  18. Mata NL, Ruiz A, Radu RA, Bui TV, Travis GH
    Chicken retinas contain a retinoid isomerase activity that catalyzes the direct conversion of all-trans-retinol to 11-cis-retinol. Biochemistry 2005 Sep 6;44(35):11715-21
  19. Mata JR, Mata NL, Tsin AT
    Substrate specificity of retinyl ester hydrolase activity in retinal pigment epithelium. Journal of lipid research 1998 Mar;39(3):604-12
  20. Mata NL, Tsin AT, Chambers JP
    Hydrolysis of 11-cis- and all-trans-retinyl palmitate by retinal pigment epithelium microsomes. The Journal of biological chemistry 1992 May 15;267(14):9794-9
  21. Blaner WS, Das SR, Gouras P, Flood MT
    Hydrolysis of 11-cis- and all-trans-retinyl palmitate by homogenates of human retinal epithelial cells. The Journal of biological chemistry 1987 Jan 5;262(1):53-8
  22. Pritsos CA
    Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chemico-biological interactions 2000 Dec 1;129(1-2):195-208
  23. Taibi G, Paganini A, Gueli MC, Ampola F, Nicotra CM
    Xanthine oxidase catalyzes the synthesis of retinoic acid. Journal of enzyme inhibition 2001;16(3):275-85
  24. Ambroziak W, Pietruszko R
    Human aldehyde dehydrogenase. Activity with aldehyde metabolites of monoamines, diamines, and polyamines. The Journal of biological chemistry 1991 Jul 15;266(20):13011-8
  25. Klyosov AA
    Kinetics and specificity of human liver aldehyde dehydrogenases toward aliphatic, aromatic, and fused polycyclic aldehydes. Biochemistry 1996 Apr 9;35(14):4457-67
  26. Grun F, Hirose Y, Kawauchi S, Ogura T, Umesono K
    Aldehyde dehydrogenase 6, a cytosolic retinaldehyde dehydrogenase prominently expressed in sensory neuroepithelia during development. The Journal of biological chemistry 2000 Dec 29;275(52):41210-8
  27. Rexer BN, Zheng WL, Ong DE
    Retinoic acid biosynthesis by normal human breast epithelium is via aldehyde dehydrogenase 6, absent in MCF-7 cells. Cancer research 2001 Oct 1;61(19):7065-70
  28. Gagnon I, Duester G, Bhat PV
    Kinetic analysis of mouse retinal dehydrogenase type-2 (RALDH2) for retinal substrates. Biochimica et biophysica acta 2002 Apr 1;1596(1):156-62
  29. Kathmann EC, Naylor S, Lipsky JJ
    Rat liver constitutive and phenobarbital-inducible cytosolic aldehyde dehydrogenases are highly homologous proteins that function as distinct isozymes. Biochemistry 2000 Sep 12;39(36):11170-6
  30. Wang X, Penzes P, Napoli JL
    Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli. Recognition of retinal as substrate. The Journal of biological chemistry 1996 Jul 5;271(27):16288-93
  31. Moore SA, Baker HM, Blythe TJ, Kitson KE, Kitson TM, Baker EN
    Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. Structure (London, England) 1998 Dec 15;6(12):1541-51
  32. Duell EA, Astr??m A, Griffiths CE, Chambon P, Voorhees JJ
    Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro. The Journal of clinical investigation 1992 Oct;90(4):1269-74
  33. Muindi JF, Young CW
    Lipid hydroperoxides greatly increase the rate of oxidative catabolism of all-trans-retinoic acid by human cell culture microsomes genetically enriched in specified cytochrome P-450 isoforms. Cancer research 1993 Mar 15;53(6):1226-9
  34. Nadin L, Murray M
    Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochemical pharmacology 1999 Oct 1;58(7):1201-8
  35. Chen H, Fantel AG, Juchau MR
    Catalysis of the 4-hydroxylation of retinoic acids by cyp3a7 in human fetal hepatic tissues. Drug metabolism and disposition: the biological fate of chemicals 2000 Sep;28(9):1051-7
  36. Marill J, Cresteil T, Lanotte M, Chabot GG
    Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Molecular pharmacology 2000 Dec;58(6):1341-8
  37. Choudhary D, Jansson I, Stoilov I, Sarfarazi M, Schenkman JB
    Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1. Drug metabolism and disposition: the biological fate of chemicals 2004 Aug;32(8):840-7
  38. McSorley LC, Daly AK
    Identification of human cytochrome P450 isoforms that contribute to all-trans-retinoic acid 4-hydroxylation. Biochemical pharmacology 2000 Aug 15;60(4):517-26
  39. Cheng Z, Radominska-Pandya A, Tephly TR
    Studies on the substrate specificity of human intestinal UDP- lucuronosyltransferases 1A8 and 1A10. Drug metabolism and disposition: the biological fate of chemicals 1999 Oct;27(10):1165-70
  40. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR
    Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug metabolism and disposition: the biological fate of chemicals 1998 Jun;26(6):507-12
  41. Samokyszyn VM, Gall WE, Zawada G, Freyaldenhoven MA, Chen G, Mackenzie PI, Tephly TR, Radominska-Pandya A
    4-hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7. The Journal of biological chemistry 2000 Mar 10;275(10):6908-14
  42. Yamashita S, Nomoto T, Ohta T, Ohki M, Sugimura T, Ushijima T
    Differential expression of genes related to levels of mucosal cell proliferation among multiple rat strains by using oligonucleotide microarrays. Mammalian genome : official journal of the International Mammalian Genome Society 2003 Dec;14(12):845-52
  43. Lindqvist A, Andersson S
    Biochemical properties of purified recombinant human beta-carotene 15,15'-monooxygenase. The Journal of biological chemistry 2002 Jun 28;277(26):23942-8
  44. Wyss A
    Carotene oxygenases: a new family of double bond cleavage enzymes. The Journal of nutrition 2004 Jan;134(1):246S-250S
  45. Lindqvist A, He YG, Andersson S
    Cell type-specific expression of beta-carotene 9',10'-monooxygenase in human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2005 Nov;53(11):1403-12