Enzymology of retinoic acid biosynthesis and degradation

Abstract

This article is available online at http://www.jlr.org ( 10 ), and regulation of energy homeostasis ( 11,12 ). atRA exerts its actions by serving as an activating ligand of nuclear atRA receptors [retinoid acid receptor (RAR) ␣ , RAR ␤ , and RAR ␥ ] and peroxisome proliferator-activated receptors (PPAR) ␤ / ␦ , which form heterodimers with retinoid X receptors ( 13,14 ). The actions of the RARs are described in more detail in this thematic series by RochetteEgly and colleagues. The concentration of atRA during embryonic development is tightly controlled in a spatial and temporal manner, and in adult tissues, it is maintained within a very narrow range that is specifi c for each given tissue. If the control mechanisms fail and the concentration of atRA exceeds or falls below the optimal range, tissues and cells undergo pathophysiological changes that in most severe cases can lead to disease. Thus, the maintenance of optimal atRA levels is essential for life. This review focusses on recent fi ndings regarding the mechanisms that control atRA homeostasis, with specifi c emphasis on the enzymes involved in atRA biosynthesis and degradation. All-trans -retinoic acid (atRA) is a highly potent derivative of vitamin A that is required for virtually all essential physiological processes and functions because of its involvement in transcriptional regulation of over 530 different genes ( 1, 2 ). For example, atRA is necessary for differentiation and development of fetal and adult tissues, stem cell differentiation, and apoptosis ( 3-7 ), and for support of reproductive functions ( 8, 9 ), immune response

Retinol and retinyl esters: biochemistry and physiology

“…This catabolism is catalyzed by one of several cytochrome P450 (CYP) enzymes (14)(15)(16)(17)(18), giving rise to more water-soluble oxidized and conjugated retinoid forms that can be more easily excreted. These CYPs are discussed in depth by Kedishvili in a review in this thematic review series ( 19 ). The metabolism of retinoids described above and the enzymes responsible for catalyzing this metabolism are summarized in Fig.…”

Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids

“…Conversion of retinol to atRA initially involves the oxidation to atRAL and subsequent oxidation of the retinal to atRA. In this respect, the enzymes alcohol dehydrogenases (ADH) and retinol dehydrogenases (RDH) have been reported to act in the formation of retinal ( 39 ). Retinal dehydrogenases (RALDH) catalyze the oxidation of retinal to retinoic acid.…”

The Retinaldehyde Reductase Activity of DHRS3 Is Reciprocally Activated by Retinol Dehydrogenase 10 to Control Retinoid Homeostasis

“…The inducibility of CYP26 gene expression by atRA provides an effective mechanism that insures the concentration of atRA does not exceed certain levels (3). However, recent studies suggest that, in addition to CYP26-mediated control, the cells and tissues have a mechanism to prevent excessive amounts of atRA at the level of its biosynthesis (4).…”

“…The overall rate of atRA biosynthesis is determined by the first step: the oxidation of retinol to retinaldehyde (5). Studies in intact living cells indicate that there are two types of retinoid oxidoreductases present in the cells at the same time: one type (NAD ϩ -preferring) oxidizes retinol to retinaldehyde, whereas the second type (NADPHpreferring), reduces retinaldehyde back to retinol (4). Together, these opposing activities appear to control the steady-state levels of retinaldehyde, the immediate precursor for atRA biosynthesis.…”