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Supplement: Proceedings of Symposium to Honor the Memory of James Allen Olson

Carotene Oxygenases: A New Family of Double Bond Cleavage Enzymes¹

DSM Nutritional Products, Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland

²To whom correspondence should be addressed. E-mail: Adrain.Wyss{at}dsm.com.

	ABSTRACT

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
ß,ß-carotene 15,15'-monooxygensae (ßCMOOX) is the key enzyme involved in the metabolism of provitamin A carotenoids to retinal. Although the enzyme has been known for >40 y, it has been only within the last 2 y that the cloning and the molecular characterization of the ßCMOOX from several species was reported in literature. New clones of the carotene metabolizing enzyme have emerged, all belonging to the family of double bond cleavage enzymes, suggesting common ancestry. ßCMOOX cleaves ß,ß-carotene to retinal in an in vitro activity assay; no apo-carotenals were identified. The second enzyme involved in carotenoid metabolism, ß,ß-carotene 9',10'-dioxygenase, is responsible for the excentric cleavage pathway of carotenoids, cleaving ß,ß-carotene to 10'-apo-carotenal and ß-ionone. In an expression overview, the ßCMOOX was detected in duodenum, liver, kidney and in the lungs of chickens. In mice, the mRNA for the central cleavage enzyme was highly expressed in liver, testes, small intestine, and kidney. ßCMOOX expression was highest in epithelial and endothelial structures in both species. These results suggest that the source of vitamin A originates from carotenoids in the corresponding tissues, in addition to retinol supplied from liver stores.

KEY WORDS: • ß,ß-carotene • vitamin A • retinal • central cleavage

The key step in vitamin A formation is the oxidative central cleavage of ß,ß-carotene into two molecules of retinal, a reaction which is catalyzed by ß,ß-carotene 15,15'-monooxygenase (ßCMOOX, formerly ß,ß-carotene 15,15'-dioxygenase, EC 1.13.11.21). Although the enzyme was characterized almost 40 y ago (1,2), it was only recently partially purified following the successful cloning of cDNAs encoding the chicken (3,4), the mouse (4–6), the Drosophila (7) and the human (8) enzymes.

Early biochemical characterization of the central cleavage enzyme suggested a dioxygenase reaction mechanism (1,9,10). More recent work has demonstrated, however, that the central cleavage of ß,ß-carotene follows a monooxygenase mechanism (11). As a result, the terminology and EC number of the enzyme will be changed accordingly to match these new findings.

Early studies demonstrated that the enzyme is cytosolic and that its activity depends on ferrous iron (10). More recent work suggests that one or more cellular cofactors are also essential to confer the full activity for the mammalian enzyme (6).

In mammals, the highest carotene-monooxygensae activity was found in the intestinal mucosa (12–14); however, enzyme activity has also been described in the liver by several groups (15,16) as well as in the lung, kidney and brain (16).

Of over 600 known carotenoids in nature, 50–60 display provitamin A activity. Among these, ß,ß-carotene is the most important for animal and human nutrition. However, there are marked species differences in carotenoid absorption and/or metabolism. In humans, the majority of absorbed ß,ß-carotene (60–70%) is believed to be converted directly to retinal after absorption (17), while the remainder is absorbed intact and deposited in the liver and adipose tissues. In rodents, ß,ß-carotene is entirely cleaved to retinal, leaving no intact ß,ß-carotene in circulation.

	Central versus excentric cleavage of ß,ß-carotene

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
Since Glover proposed an excentric cleavage mechanism in 1960 (18), there has been an ongoing debate regarding the two possible cleavage pathways leading to vitamin A (19). Early work by Sharma et al. (20) also suggested a significant role for the excentric cleavage pathway in the ß,ß-carotene metabolism. Despite evidence for an excentric cleavage pathway, the central cleavage mechanism leading to the formation of retinal was the more widely accepted metabolic pathway for retinoid formation until Wang et al. (21–23) provided evidence for in vivo and in vitro production of apo-carotenals and retinoic acid as the main products of ß,ß-carotene cleavage. It has been proposed that the apo-carotenals formed by the excentric cleavage are subsequently shortened through a ß-oxidation-like mechanism resulting in the formation of one molecule of retinoic acid per molecule of ß,ß-carotene.

More recently, von Lintig and colleagues (24) published the cloning and molecular characterization of an enzyme responsible for the excentric cleavage of ß,ß-carotene in mammals. The enzyme, belonging to the new family of double bond cleavage enzymes, catalyzes the cleavage of ß,ß-carotene at the 9',10' double bond resulting in the formation of ß-apo-10'-carotenal and ß-ionone. With the molecular characterization of this enzyme, we have another powerful tool to investigate the mechanisms of vitamin A formation following an alternative pathway. Finally, the debate about ß,ß-carotene cleavage has been settled as both pathways were demonstrated to be important in nature. Each pathway is used preferentially in mammalian ß,ß-carotene metabolism, depending on the specific tissue.

	Cloning of the chicken and mouse ß,ß-carotene 15,15'-monooxygenase cDNA

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
Enriched ßCMOOX was obtained from chicken intestinal mucosa extracts so that partial amino acid sequences could be determined by Matrix-Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectrometry. Two peptide sequences were subsequently used to obtain cDNA sequences for the chicken ßCMOOX by reverse genetics. Following two rounds of PCR and RT-PCR, respectively, a cDNA band of 597 bp was obtained and used to screen a cDNA library from chicken duodenum. A full-length cDNA of 3.1 kb encoding a 60.4 kDa protein was successfully cloned and expressed in E. coli and in a human duodenal cell line, as well as in two rodent cell lines (3). The recombinant protein was tested for cleavage activity and incubated with ß,ß-carotene in vitro. Retinal was the only reaction product in the monooxygensae activity assay, and no other metabolites, such as ß-apo-carotenal, were detected, thus confirming the activity of the ß,ß-carotene central cleavage enzyme. By searching the EMBL gene bank, we identified a mouse EST (EMBL accession no. AW044715) which contained the putative mouse homologue of ßCMOOX. This cDNA was also cloned, sequenced, expressed in E. coli and resubmitted to the genebank (EMBL accession no. AW278064).

	Expression pattern of ß,ß-carotene-15,15'-monooxygenase

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
The expression pattern of the ßCMOOX was established in chicken and mouse tissues using a combination of Northern blotting and in situ hybridization (4). In chicken, ßCMOOX mRNA was localized primarily in duodenal villi as well as in lung, liver and in tubular structures of the kidney (Fig. 1). These findings demonstrate that the ßCMOOX is specifically expressed in epithelial and tubular structures, where it may act to provide the local source of vitamin A. The mRNA for the ßCMOOX was therefore detectable in the specific tissues, where its activity was demonstrated earlier in previous studies (16). In addition, ßCMOOX mRNA was also detected in chicken spleen and in T-cells of the duodenum.

View larger version (117K): [in this window] [in a new window]   FIGURE 1 In situ hybridization on chicken cryosections [this figure is derived from (4)]. Strong signals were obtained in epithelial cells of duodenal crypts and villi (a). In lung (b) the epithelial cells of bronchioles were strongly stained, whereas the alveolar cells were negative. A diffuse, positive signal was detected in liver hepatocytes (c). The epithelial layers of glomeruli (G) were strongly stained in kidney (d). Most of the tubuli were only weakly positive; however, some (T) gave a stronger signal. The endothelium of blood vessels (B) was also stained in kidney. All sections were magnified x100.

View larger version (27K): [in this window] [in a new window]   FIGURE 2 Taqman RT-PCR analysis of mouse ß,ß-carotene 15,15'-monooxygenase in different tissues. The expression levels of ßCMOOX were normalized to duodenum. In the liver and testes, high expression levels were found. Comparable levels of mRNA were also detected in the ileum. In kidney, thymus and retina the ßCMOOX mRNA was also detectable, whereas in the other tissues it was not quantifiable anymore. Tissues were taken from an NMRI mouse.

View larger version (66K): [in this window] [in a new window]   FIGURE 3 Immunhistochemistry of chicken duodenum. Panel a) shows an overview of a duodenal section, magnification x50, stained with a chicken peptide antibody against ßCMOOX. Panel b) depicts a section of a) with a x200 magnification. ß,ß-carotene 15,15'-monooxygenase expression is differentiation dependent and appears to be highest at the tip of the villus. The sections were counterstained with hematoxylin.

	In vivo regulation of vitamin A formation

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

Parvin demonstrated that the nutritional status of rats can clearly affect the ßCMOOX activity (28). In vitamin A deficient animals, the ßCMOOX enzyme activity was more than double the activity found in the control animals, whereas animals fed a low protein diet had 25% the monooxygenase activity of the control animals.

Further evidence of ßCMOOX regulation has been found by investigating its enzymatic activity in the TC7 clone of the human CaCo-2 cell line. The TC7 clone is the only eukaryotic cell line in which ßCMOOX activity could be quantified. During et al. (29) have shown that FCS levels in cell culture media, differentiation state of the cells and treatment with ß,ß-carotene increased the enzymatic activity moderately, which suggests that the ß,ß-carotene 15,15'-monooxygenase is regulated by various compounds.

With respect to the regulation of this key step in vitamin A formation, we have recently demonstrated that RA decreases the activity of intestinal ßCMOOX and down-regulates the mRNA level in chickens and rats (Bachmann et al., submitted). Animals raised on a vitamin A deficient diet were treated with a single dose of RA for four consecutive days. After sacrificing the animals, ßCMOOX activity and mRNA levels were quantified. In chicken and rats, intestinal ßCMOOX mRNA levels were downregulated up to 90% (Bachmann et al., unpublished results). However, feeding rats with an antagonist of RAR resulted in a slight increase in the enzyme’s activity. This is the first molecular evidence for a transcriptional/translational regulation of the ß,ß-carotene cleavage reaction, involving possibly two or more members of the retinoic acid receptor family, which exhibit their action as ligand induced transcription factors. This regulation may contribute to the maintainance of vitamin A homeostasis in vertebrates. Thus far, regulation has been demonstrated exclusively in duodenum, whereas in liver and kidney, the enzyme has not been found to be regulated.

	Homologies between the different species

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
Comparison of the deduced amino acid sequences revealed that the human, mouse, chicken and the Drosophila enzymes all share overall sequence homology with a distinct pattern of highly identical conserved stretches (8). In addition, human ßCMOOX also shares 53% sequence homology with human RPE65 protein, suggesting a related function between the two proteins. Although the exact function of RPE65 that was first described in bovine eyes (31) is not yet known, a role in vitamin A metabolism has been proposed (32). Mutations in the RPE65 gene are known to be responsible for a severe form of early onset retinal dystrophy; however, direct biochemical evidence for the function of RPE65 has not been found. It remains to be investigated as to whether the homology between carotene oxygenases and RPE65 is due to a conserved carotenoid/retinoid binding motif or because of a related biochemical function, e.g., cleavage of carotenoids.

In addition to the homology among the ß,ß-carotene cleavage enzymes of higher animals, enzymes from C. elegans, Arabidopsis thaliana or Synechococcus (Fig. 4) also share significant homology with the mammalian ß,ß-carotene cleavage enzymes. Vp14, which shares weak sequence homology to the animal ß,ß-carotene 15,15'-monooxygenase, catalyzes the oxidative cleavage of 9-cis neoxhanthin in the biosynthetic pathway of the plant hormone abscisic acid (33). Vp14 was the first carotenoid cleavage enzyme that was identified on a molecular level. Several other examples of excentric carotenoid cleavage also exist, including the formation of saffron in crocus.

View larger version (25K): [in this window] [in a new window]   FIGURE 4 Phylogenetic tree with some members of the new family of double bond cleavage enzymes. The dendrogram was created using the PileUp program, included in the Genetics Computer Group software package (University of Madison, WI). The PileUp program performs a pairwise alignment that scores the similarity between every possible pair of amino acid sequences. These assigned similarity scores are used to create a clustering order that are represented by the dendrogram. The distance along the horizontal axis is proportional to the differences between the sequences of the various species. The shorter the distance between two species, the higher the homology between the two carotenoid cleavage enzymes. The ßCMOOX homologues build a subgroup, as do the excentric cleavage enzymes.

	Future prospects

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 
Vitamin A deficiency is a serious concern in the developing countries, affecting 140–250 million people worldwide. Subclinical manifestations of lacking vitamin A include night blindness, whereas more severe deficiencies can lead to corneal malformations, e.g., xerophthalmia and keratomalacia, as well as a higher susceptibility to infectious diseases. The benefits of vitamin A and ß-carotene supplementation to combat vitamin A deficiency have been demonstrated in several studies (36–38). Increased molecular understanding of vitamin A formation, storage and metabolism in humans will hopefully contribute towards the goal of overcoming vitamin A deficiency diseases.

Since the cloning of the two carotene cleavage enzymes, previously unanswered questions regarding vitamin A research, in particular, on the molecular level, can now be addressed. This includes tissue specificity of vitamin A formation either by the central or the excentric cleavage pathway, the regulation of vitamin A homeostasis as well as the impact of vitamin A formation on cell differentiation, and the developmental processes mediated by retinoic acid during embryogenesis.

	ACKNOWLEDGMENTS

 
I want to thank all collaborators at DSM Nutritional Products and at the Institute of Organic Chemistry, University of Basel, and Jennifer Bryant for carefully proofreading the manuscript.

	FOOTNOTES

 
¹ Presented as part of the James Allen Olson Memorial Symposium, "Functions and Actions of Retinoids and Carotenoids" held at Iowa State University, June 21–24, 2001 to honor the memory of James Allen Olson. This conference was supported by the U.S. Department of Agriculture; National Institutes of Health; Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University (ISU); Department of Food Science and Human Nutrition, ISU; College of Liberal Arts and Sciences, ISU; F. Hoffmann-La Roche; Kemin Foods, L.C., Procter & Gamble Company; Lipton; Best Foods; BASF; SmithKline Beecham; Cognis Corporation; Allergen and INEXA. Guest editor for this symposium was Norman I. Krinsky, Department of Biochemistry, School of Medicine, and the Jean Mayer Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111-1837.

	LITERATURE CITED

TOP ABSTRACT Central versus excentric... Cloning of the chicken... Expression pattern of... In vivo regulation of... Homologies between the different... Future prospects LITERATURE CITED

 

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