Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewMammalian Carotenoid-oxygenases: Key players for carotenoid function and homeostasis☆
Section snippets
Out of the wild green yonder: carotenoid cleaving enzymes
Vitamin A was recognized as an essential factor in food a century ago. Early research suggested that certain yellow plant pigments had the same activity as vitamin A. This phenomenon was explained in 1930 by Moore [11], who described a conversion of β,β-carotene into vitamin A in the small intestine of the rat, thus providing the first evidence that a plant-derived carotenoid is the direct precursor of retinoids. Karrer [12] elucidated the structure of β,β-carotene and proposed a central
Mammalian genomes encode three different CCE family members
In mammals, three different members of the CCE family have been molecularly identified and biochemically characterized. RPE65 is expressed in the retinal pigment epithelium of the eyes and localizes to the endoplasmatic reticulum. The critical role of RPE65 in visual chromophore production and regeneration is well established and has been extensively reviewed (e.g., [23]). The other two family members, BCMO1 and β,β-carotene-9,10-dioxygenase 2 (BCDO2), are true carotenoid-oxygenases and
BCMO1 is the key enzyme for vitamin A production
In mammals, the molecular and biochemical basis of vitamin A function has been well established. The vitamin A-derivative 11-cis-retinal serves as chromophore of cone and rod visual pigments [40]. Moreover, vitamin A is the precursor for all-trans-retinoic acid (RA), which is required for a wide range of biological processes, including embryonic and fetal development, cell differentiation and metabolic control. This hormone-like compound is the ligand of retinoic acid receptors (RARs) that
Regulation of intestinal vitamin A production
The small intestine is responsible for absorbing dietary lipids such as carotenoids and delivering them to the organism as triglyceride-rich lipoproteins. Intestinal lipid absorption is a complex process that evidently depends on membrane receptors/transporters [46]. For carotenoids, it is now clear that scavenger receptors such as SR-B1 and CD36 facilitate their absorption [47]. Additionally, SR-BI also facilitates the intestinal absorption of tocopherols (vitamin E) [48]. Studies in a
BCMO1 expression in peripheral tissues and the embryo
In humans, substantial amounts of absorbed β-carotene are not cleaved in the intestine by BCMO1 (up to 40% of dietary intake) [52] and along with other lipids become incorporated in chylomicrons and found associated with circulating lipoproteins [53]. Circulating carotenoids in association with lipoproteins can be then taken up by the lipoprotein specific receptors. In mice, BCMO1 is expressed in both the intestine and liver but also in peripheral tissues, including the mammalian embryo [10],
BCMO1 deficiency affects embryonic retinoid metabolism
Loredana Quadro and coworkers provided evidence that BCMO1 can maintain retinoid homeostasis in embryonic tissues of VAD mice [71]. In an elegant genetic approach, they generated RBP−/− BCMO1−/− double mutant female mice. In RBP-deficiency, mice depend on a continuous dietary vitamin A supply (RE in chylomicrons) [75]. These double mutant mice were crossed with RBP−/− male mice so that dames were deficient both for RBP and BCMO1 whereas their offspring carried a functional BCMO1 allele.
A role of BCMO1 in the regulation of body fat reserves
Among the many functions attributed to retinoids, its putative role in adipocyte biology and the regulation of body fat reserves has generated clinical and scientific interest. The vitamin A derivative RA acid has been shown to influence adipocyte differentiation [77], [78] and fat deposition [79], mitochondrial uncoupling [80], [81], oxidative metabolism [82], [83] and adipokine expression [84], [85], [86], [87] in adipose tissues. These effects are mediated in part via the classical retinoic
BCDO2 and apocarotenoid signaling molecules
Though the role of BCMO1 for retinoid metabolism has been well established, less is known about the second carotenoid-oxygenase, BCDO2. As described above, biochemical studies indicate that this enzyme displays broad substrate specificity and converts both carotenes and xanthophylls by oxidative cleavage at the 9′,10′ and 9,10 double bonds. Apocarotenoids such as β-14′-apocarotenal and β-13′-apocarotenal have shown to influence the activities of nuclear receptors such RXR and PPARα and γ [104],
BCDO2, carotenoid homeostasis, and mitochondria
The broad substrate specificity of BCDO2 implicates this enzyme in the metabolism of both carotene and xanthophylls. A critical role of BCDO2 for xanthophyll metabolism was substantiated by findings in chickens. The yellow skin color of chickens (xanthophylls) is determined by cis-acting and tissue-specific regulatory mutation(s) that inhibit expression of BCDO2 in skin [111]. Additionally, it was shown that mutations in BCDO2 gene cause the yellow fat phenotype (xanthophyll accumulation) of
Concluding remarks
A ubiquitous family of non-heme iron oxygenases has been identified that modify double bonds of carotenoids and their apocarotenoid derivatives by trans-to-cis isomerization and oxidative cleavage. Mammalian genomes encode three distinct family members. RPE65 is the isomerase in the visual cycle, whereas BCMO1 and BCDO2 catalyze the oxidative cleavage of carotenoids. BCMO1 cleaves at the C15,C15′ double bond and has a limited substrate specificity for proretinoid carotenoids such as
Acknowledgments
The authors would like to thank Drs. Ouliana Ziouzenkova and Earl Harrison for the invitation to contribute this article to this special issue of BBA. This work was supported by the National Institute of Health grant EY019641. Darwin Babino was supported by a visual science training grant (NIH T32-EY07157).
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This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.