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Retinol metabolism


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Retinol metabolism

Retinol metabolism

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

Rhodopsin is converted by photoabsorption to metarhodopsin, and the latter isreconverted to Rhodopsin by light. It is well known that Rhodopsin can beformed from opsin only when (11Z)-Retinal is present. The photoisomerization ofRetinal released during the degradation of metarhodopsin is catalyzed by anunknown isomerase is and this photoisomerization stereospecifically directed toward theformation of (11Z)-Retinal [2], [3]. Retinal isalso reduced in the reaction catalyzed by all -trans -retinal-specific Retinoldehydrogenases.- 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], [7], [8], [9], [10],Retinol dehydrogenase 12 (all-trans/9-cis/11-cis) ( RDH12 ) [11],[12], [13], retinol dehydrogenase 14 (all-trans/9-cis/11-cis) (RDH14 ) [1], [14], dehydrogenase/reductase (SDR family)member (RDH14) [15]. This dehydrogenase activity utilizes [H+] of NADH anddoes not require NAD + to generate Retinol. These enzymes alsocatalyze oxidizing (11Z)-Retinol with concomitant generation of [H] NADH tocomplete the cycle.

Retinol is further isomerized via inversion of the C15 prochiral methylenehydroxyl group configuration resulting in formation of (11Z)-Retinol. Thisreaction is catalyzed by specific isomerase [16], [17].

Retinol can also esterification to format Retinol palmitate and11-cis-Retinyl palmitate which can be either stored in the cell or processedfurther [18]. The 11-cis-Retinyl palmitate can be hydrolyzed at therate ~20 times faster than Retinol palmitate. Human retinal epithelium containsdistinct activities that hydrolyze 11-cis-Retinyl palmitate and Retinolpalmitate [19], [20], [18].

Retinal in turn is rapidly oxidized to Retinoic acid by Xanthinedehydrogenase ( Xanthine oxidase ) [21], [22], Aldehydedehydrogenase 2 family (mitochondrial) ( ALDH2 ) [23], [24],Aldehyde dehydrogenase 1 family, member A3 ( DHA6 ) [25], [26], Aldehyde dehydrogenase 9 family, member A1 ( ALD9A1 ), [23],Aldehyde dehydrogenase 1 family, member A2 ( DHA2 ) [27], and Aldehydedehydrogenase family 1, subfamily A7 ( AL1A7 ) [28], Aldehydedehydrogenase 1 family, member A1 ( AL1A1 ) [29], [30].Retinoic acid is metabolized to 4-Hydroxy-retinoic acid, 4-Oxo-retinoicacid and 5,6-Epoxy-retinoic acid . Oxidation of Retinoic acid to4-Hydroxy-retinoic acid is catalyzed by cytochrome P-450 isozyme(s) CytochromeP450, 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 andCYP1A2 ), 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 ), CytochromeP450, 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 ) [31], [32], [33],[34],[35], [36]. The next step of Retinoicacid oxidation results in formation of 4-Oxo-retinoic acid and is alsocatalyzed by P450 cytochromes CYP3A4, CYP1A1, CYP2C9,CYP3A7, CYP2C8, CYP3A5 and CYP4A11 [32], [37].

Glucuronic acid can be conjugated to 4-Hydroxy-retinoic acid, which results information of two types of glucuronides: 4-Hydroxy-retinoic acidO1-beta-D-glucuronoside and 4-Hydroxy-retinoic acid O4beta-D-glucuronoside.These reactions are catalyzed by UDP Glucuronosyltransferase 1 family, polypeptide A8 (UGT1A8 ) [38] and UDP Glucuronosyltransferase 1 family, polypeptide A3( UGT1A3 ) [39] to 4-Hydroxy-retinoic acidO1-beta-D-glucuronoside; and by UDP Glucuronosyltransferase 2 family, polypeptide B7( UGT2B7 ) [40] and UDP-Glucuronosyltransferase 2 family, member 37 (UDB5 ) [41] to 4-Hydroxy-retinoic acid O4beta-D-glucuronoside.

Two key enzymes involved in carotenoid metabolism are Beta-carotene15,15'-monooxygenase 1 ( BCDO ) and Beta-carotene oxygenase 2 ( BCDP ). Thefirst one cleaves Beta-Carotene to form Retinal [42], [43]. The second enzyme is responsible for the unconventional cleavage ofBeta-Carotene to form Beta-apo-10'-carotenal and Beta-Ionone [43], [44].