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Metazoan photochemistry involves cis-trans isomerization of a retinylidene chromophore bound to G protein coupled receptors. Successful production of chromophores is critical for photoreceptor function and survival. For chromophore production, animals have to choose from more than 600 naturally occurring carotenoids and process them by oxidative cleavage and geometric isomerization of double bonds. Vertebrates employ three carotenoid cleavage oxygenases to tailor the carotenoid precursor in the synthesis of 11-cis-retinal (vitamin A1). Lepidoptera (butterfly and moth) possess only one such enzyme, NinaB, which faces the challenge to catalyze these reactions in unison to produce 11-cis-3-hydroxy-retinal (vitamin A3). We here showed that key to this multitasking is a bipartite substrate recognition site that conveys regio- and stereoselectivity for double bond processing. One side performed the specific C11, C12 cis-isomerization and preferentially binds 3-OH-β-ionone rings sites. The other side maintained a trans configuration in the resulting product and preferentially binds noncanonical ionone ring sites. Concurrent binding of carotenoids containing two cyclohexyl rings to both domains is required for specific oxidative cleavage at position C15, C15 of the substrate. The unique reaction sequence follows a dioxygenase mechanism with a carbocation/radical intermediate. This ingenious quality control system guarantees 11-cis-3-hydroxy-retinal production, the essential retinoid for insect (vitamin A3) vision.

Two enzymes have been identified for the oxidative metabolism of carotenoids in mammals. Carotene-15,15'-monooxygenase (CMO-I) primarily centrally cleaves [beta],[beta]-carotene to form vitamin A. We hypothesize that carotene-9',10'-monooxygenase (CMO-II) plays a key role in metabolism of acyclic nonprovitamin A carotenoids such as lycopene. We investigated carotenoid bioaccumulation in young adult, male, wild-type (WT) mice or mice lacking CMO-II (CMO-II KO). Mice were fed an AIN-93G diet or identical diets supplemented with 10% tomato powder, 130 mg lycopene/kg diet (10% lycopene beadlets), or placebo beadlets for 4 or 30 d. Lycopene preferentially accumulated in CMO-II KO mouse tissues and serum compared with WT mouse tissues. [beta]-Carotene preferentially accumulated in some CMO-II KO mouse tissues compared with WT mouse tissues. Relative tissue mRNA expression of CMO-I and CMO-II was differentially expressed in mouse tissues, and CMO-II, but not CMO-I, was expressed in mouse prostate. In conclusion, the loss of CMO-II expression leads to increased serum and tissue concentrations of lycopene in tomato-fed mice. J. Nutr. 140: 2134-2138, 2010. doi: 10.3945/jn.110.128033.

15,15'-carotenoid monooxygenase (CMO I) is generally recognized as the central carotenoid cleavage enzyme responsible for converting provitamin A carotenoids to vitamin A, while having little affinity for nonprovitamin A carotenoids, such as lycopene. To investigate the role of CMO I in carotenoid metabolism, ~90-d-old C57BL/6 x 129/SvJ [CMO I wild-type (WT)] and B6;129S6-Bcmo1tm1Dnp [CMO I knockout (KO)] mice were fed a high-fat, moderate vitamin A, cholesterol-containing diet supplemented with 150 mg/kg diet of [beta]-carotene, lycopene, or placebo beadlets for 60 d (n = 12-14). CMO I KO mice fed lycopene (Lyc-KO) exhibited significant decreases in hepatic, spleen, and thymus lycopene concentrations and significant increases in prostate, seminal vesicles, testes, and brain lycopene concentrations compared with WT mice fed lycopene (Lyc-WT). Furthermore, in the serum and all tissues analyzed, excluding the testes, there was a significant increase in the percent lycopene cis isomers in Lyc-KO mice compared with Lyc-WT mice. CMO I KO mice fed [beta]-carotene ([beta]C-KO) had significantly lower hepatic vitamin A concentrations (17% of WT mice fed [beta]-carotene [[beta]C-WT]). Concordantly, [beta]C-KO mice had higher serum and tissue [beta]-carotene concentrations than [beta]C-WT mice. In addition, phenotypically CMO I KO mice had significantly higher final body weights and CMO I KO female mice had significantly lower uterus weights than CMO I WT mice. In conclusion, CMO I KO mice fed low levels of vitamin A have altered lycopene biodistribution and isomer patterns and do not cleave [beta]-carotene to vitamin A at appreciable levels.

[beta],[beta]-carotene 15,15'-monooxygensae ([beta]CMOOX) 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 [beta]CMOOX 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. [beta]CMOOX cleaves [beta],[beta]-carotene to retinal in an in vitro activity assay; no apo-carotenals were identified. The second enzyme involved in carotenoid metabolism, [beta],[beta]-carotene 9',10'-dioxygenase, is responsible for the excentric cleavage pathway of carotenoids, cleaving [beta],[beta]-carotene to 10'-apo-carotenal and [beta]-ionone. In an expression overview, the [beta]CMOOX 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. [beta]CMOOX 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: * [beta],[beta]-carotene * vitamin A * retinal * central cleavage

[beta],[beta]-Carotene 15,15'-monooxygenase (formerly termed [beta],[beta]-carotene 15,15'-dioxygenase, EC 1.13.11.21) catalyzes the conversion of provitamin A carotenoids to retinal in vertebrate tissues. In the present study, we investigated whether preformed vitamin A or [beta]-carotene and its direct metabolites can regulate the enzyme activity in vivo. We found dose-dependent decreases in intestinal [beta],[beta]-carotene monooxygenase activity after oral administration to rats of retinyl acetate (up to -79%), [beta]-carotene (up to -79%), apo-8'-carotenal (up to -56%), all-trans retinoic acid (up to -88%), and 9-cis retinoic acid (up to -67%). Liver [beta],[beta]-carotene 15,15'-monooxygenase ([beta]CMOOX) activity was not affected. Apo-12'carotenal and the retinoic acid receptor (RAR) [alpha] antagonist Ro 41-5253 significantly increased the intestinal enzyme activity by 55 and 94%, respectively. When [beta]-carotene was administered to rats pretreated with the two cytochrome [P.sub.450] (CYP) inducers, pentobarbital and naphthoflavone, the intestinal [beta]CMOOX activity increased by 39%. In a transcriptional study in chickens, treatment with retinoic acid resulted in low expression of the intestinal [beta]CMOOX. Our data suggest that retinoids and carotenoids might regulate [beta]CMOOX expression by a transcriptional feedback mechanism via interaction with members of the RAR family. J. Nutr. 132: 3616-3622, 2002. KEY WORDS: * [beta]-carotene cleavage * retinoic acid regulation * RAR[alpha] * rats * chickens

Two distinct nuclear signalling pathways for vitamin D are activated respectively by the vitamin D receptor alone or in conjunction with the receptor's heterodimers and the retinoid-X receptor-alpha. An analysis of both Drosophila and mammalian cells was used to obtain these results that support the existence of two vitamin D response element classes.