Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism
Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism
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DOI：
10.1074/jbc.m113.501049
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发表时间：
2013-11-22
影响因子：
4.8
通讯作者：
von Lintig, Johannes
中科院分区：
文献类型：
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作者：
Amengual, Jaume;Widjaja-Adhi, M. Airanthi K.;von Lintig, Johannes
背景：哺乳动物基因组编码两种类胡萝卜素加氧酶，但它们对维生素A稳态的贡献尚不清楚。结果：哺乳动物利用对称和偏心裂解类胡萝卜素加氧酶将不同的维生素A原类胡萝卜素转化为维生素A。结论：两种类胡萝卜素加氧酶均参与维生素A的合成。意义：类胡萝卜素是人类饮食中维生素A的主要来源。哺乳动物基因组编码两种维生素A原转换酶：-胡萝卜素-15，15-加氧酶(BCO1)和-胡萝卜素-9，10-加氧酶(BCO2)。BCO1的对称裂解产生维甲酸类化合物(-15-阿糖类胡萝卜素，C-20)，而BCO2的偏心裂解产生长链的(>；C-20)阿普胡萝卜素。在这里，我们使用遗传和生化方法来阐明这些酶对维生素A原代谢的贡献。我们让野生型、Bco1(-/-)、Bco2(-/-)和Bco1(-/-)Bco2(-/-)双基因敲除小鼠接受控制饮食，提供胡萝卜素作为产生类胡萝卜素的唯一来源。这项研究揭示了BCO1对维甲酸的动态平衡至关重要。BCO1的遗传破坏导致-胡萝卜素积累和维生素A缺乏，并伴随着BCO2依赖的少量-apo-10-胡萝卜素(APO10ol)的产生。我们发现APO10ol可以被与维生素A相同的蛋白质酯化和运输，但亲和力较低，反应动力学较慢。在野生型小鼠中，APO10ol被BCO1转化为维甲酸。我们还表明，BCO2和BCO1以APO10ol为中间体逐步切割可以提供一种机制来定制不对称类胡萝卜素，如隐黄素，用于生产维生素A。综上所述，我们的研究提供了哺乳动物利用两种类胡萝卜素加氧酶从维生素A原类胡萝卜素合成维甲酸的证据。
Background: Mammalian genomes encode two carotenoid oxygenases, but their contributions to vitamin A homeostasis remain undefined. Results: Mammals employ symmetric and eccentric cleaving carotenoid oxygenases to convert different provitamin A carotenoids to vitamin A. Conclusion: Both carotenoid oxygenases contribute to vitamin A production. Significance: Carotenoids are the major source for vitamin A in the human diet.Mammalian genomes encode two provitamin A-converting enzymes as follows: the -carotene-15,15-oxygenase (BCO1) and the -carotene-9,10-oxygenase (BCO2). Symmetric cleavage by BCO1 yields retinoids (-15-apocarotenoids, C-20), whereas eccentric cleavage by BCO2 produces long-chain (>C-20) apocarotenoids. Here, we used genetic and biochemical approaches to clarify the contribution of these enzymes to provitamin A metabolism. We subjected wild type, Bco1(-/-), Bco2(-/-), and Bco1(-/-)Bco2(-/-) double knock-out mice to a controlled diet providing -carotene as the sole source for apocarotenoid production. This study revealed that BCO1 is critical for retinoid homeostasis. Genetic disruption of BCO1 resulted in -carotene accumulation and vitamin A deficiency accompanied by a BCO2-dependent production of minor amounts of -apo-10-carotenol (APO10ol). We found that APO10ol can be esterified and transported by the same proteins as vitamin A but with a lower affinity and slower reaction kinetics. In wild type mice, APO10ol was converted to retinoids by BCO1. We also show that a stepwise cleavage by BCO2 and BCO1 with APO10ol as an intermediate could provide a mechanism to tailor asymmetric carotenoids such as -cryptoxanthin for vitamin A production. In conclusion, our study provides evidence that mammals employ both carotenoid oxygenases to synthesize retinoids from provitamin A carotenoids.