Specificity of Zebrafish Retinol Saturase: Formation of All-trans-13,14-dihydroretinol and All-trans-7,8- dihydroretinol

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• 作者：Alexander R. Moise ; Andrea Isken ; Marta Domí ; nguez ; Angel R. de Lera ; Johannes von Lintig ; Krzysztof Palczewski
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：February 20, 2007
• 年：2007
• 卷：46
• 期：7
• 页码：1811 - 1820
• 全文大小：976K
• 年卷期：v.46,no.7(February 20, 2007)
• ISSN：1520-4995

文摘

Metabolism of vitamin A, all-trans-retinol, leads to the formation of 11-cis-retinaldehyde, thevisual chromophore, and all-trans-retinoic acid, which is involved in the regulation of gene expressionthrough the retinoic acid receptor. Enzymes and binding proteins involved in retinoid metabolism arehighly conserved across species. We previously described a novel mammalian enzyme that saturates the13-14 double bond of all-trans-retinol to produce all-trans-13,14-dihydroretinol, which then follows thesame metabolic fate as that of all-trans-retinol. Specifically, all-trans-13,14-dihydroretinol is transientlyoxidized to all-trans-13,14-dihydroretinoic acid before being oxidized further by Cyp26 enzymes. Here,we report the identification of two putative RetSat homologues in zebrafish, one of which, zebrafishRetSat A (zRetSat A), also had retinol saturase activity, whereas zebrafish RetSat B (zRetSat B) wasinactive under similar conditions. Unlike mouse RetSat (mRetSat), zRetSat A had an altered bond specificitysaturating either the 13-14 or 7-8 double bonds of all-trans-retinol to produce either all-trans-13,14-dihydroretinol or all-trans-7,8-dihydroretinol, respectively. zRetSat A also saturated the 13-14 or 7-8double bonds of all-trans-3,4-didehydroretinol (vitamin A2), a second endogenous form of vitamin A inzebrafish. The dual enzymatic activity of zRetSat A displays a newly acquired specificity for the 13-14double bond retained in higher vertebrates and also the evolutionarily preserved activity of bacterial phytoenedesaturases and plant carotenoid isomerases. Expression of zRetSat A was restricted to the liver andintestine of hatchlings and adult zebrafish, whereas zRetSat B was expressed in the same tissues but atearlier developmental stages. Exogenous all-trans-retinol, all-trans-13,14-dihydroretinol, or all-trans-7,8-dihydroretinol led to the strong induction of the expression of the retinoic acid-metabolizing enzyme,Cyp26A1, arguing for an active signaling function of dihydroretinoid metabolites in zebrafish. Thesefindings point to a conserved function but altered specificity of RetSat in vertebrates, leading to thegeneration of various dihydroretinoid compounds, some of which could have signaling functions.