title: Evidence for compartmentalization of mammalian carotenoid metabolism.
abstract: The critical role of retinoids (vitamin A and its derivatives) for vision, reproduction, and survival has been well established. Vitamin A is produced from dietary carotenoids such as β-carotene by centric cleavage via the enzyme BCO1. The biochemical and molecular identification of a second structurally related β-carotene metabolizing enzyme, BCO2, has led to a prolonged debate about its relevance in vitamin A biology. While BCO1 cleaves provitamin A carotenoids, BCO2 is more promiscuous and also metabolizes nonprovitamin A carotenoids such as zeaxanthin into long-chain apo-carotenoids. Herein we demonstrate, in cell lines, that human BCO2 is associated with the inner mitochondrial membrane. Different human BCO2 isoforms possess cleavable N-terminal leader sequences critical for mitochondrial import. Subfractionation of murine hepatic mitochondria confirmed the localization of BCO2 to the inner mitochondrial membrane. Studies in BCO2-knockout mice revealed that zeaxanthin accumulates in the inner mitochondrial membrane; in contrast, β-carotene is retained predominantly in the cytoplasm. Thus, we provide evidence for a compartmentalization of carotenoid metabolism that prevents competition between BCO1 and BCO2 for the provitamin and the production of noncanonical β-carotene metabolites.
authors.affiliation: Department of Biochemistry.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Palczewski
authors.affiliation: Department of Pharmacology, and.
authors.forename: Jaume
authors.initials: J
authors.lastname: Amengual
authors.affiliation: Department of Pharmacology, and Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.affiliation: Department of Pharmacology, and jxv99@case.edu.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism*; D049308:Dioxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals; D065146:Zeaxanthins / Q000378:metabolism*; D019207:beta Carotene / Q000378:metabolism*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D021382:Protein Sorting Signals; D065146:Zeaxanthins; D019207:beta Carotene; D049308:Dioxygenases; C493359:Bco1 protein, mouse; C506534:BCO2 protein, human; D050559:beta-Carotene 15,15'-Monooxygenase
keywords: BCO1; BCO2; vitamin A; zeaxanthin; β-carotene