Pathway maps

Retinol metabolism
Retinol metabolism

Object List (links open in MetaCore):

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].


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