Xanthophylls Modulate Palmitoylation of Mammalian β-Carotene Oxygenase 2

Abstract

An extensive body of work has documented the antioxidant role of xanthophylls (lutein and zeaxanthin) in human health and specifically how they provide photoprotection in human vision. More recently, evidence is emerging for the transcriptional regulation of antioxidant response by lutein/lutein cleavage products, similar to the role of β-carotene cleavage products in the modulation of retinoic acid receptors. Supplementation with xanthophylls also provides additional benefits for the prevention of age-related macular degeneration (AMD) and attenuation of Alzheimer’s disease symptoms. Mammalian β-carotene oxygenase 2 (BCO2) asymmetrically cleaves xanthophylls as well as β-carotene in vitro. We recently demonstrated that mouse BCO2 (mBCO2) is a functionally palmitoylated enzyme and that it loses palmitoylation when cells are treated with β-carotene. The mouse enzyme is the easiest model to study mammalian BCO2 because it has only one isoform, unlike human BCO2 with several major isoforms with various properties. Here, we used the same acyl-RAC methodology and confocal microscopy to elucidate palmitoylation and localization status of mBCO2 in the presence of xanthophylls. We created large unilamellar vesicle-based nanocarriers for the successful delivery of xanthophylls into cells. We demonstrate here that, upon treatment with low micromolar concentration of lutein (0.15 µM), mBCO2 is depalmitoylated and shows partial nuclear localization (38.00 ± 0.04%), while treatment with zeaxanthin (0.45 µM) and violaxanthin (0.6 µM) induces depalmitoylation and protein translocation from mitochondria to a lesser degree (20.00 ± 0.01% and 35.00 ± 0.02%, respectively). Such a difference in the behavior of mBCO2 toward various xanthophylls and its translocation into the nucleus in the presence of various xanthophylls suggests a possible mechanism for transport of lutein/lutein cleavage products to the nucleus to affect transcriptional regulation.

Structure-Function-Environment Relationship of the Isomers Zeaxanthin and Lutein

“…However, more work is needed to clarify whether these xanthophylls act by modulating redox-signaling pathways or by binding directly to ligand-activated receptor proteins that function in gene regulation. The possibility has been suggested that the cleavage products of zeaxanthin and lutein [105] may bind to such ligand-activated receptors [106,107]. The oxidation products of carotenoids may also act as signaling molecules in plants [16].…”

Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants

“…In addition, very recently, it was also reported that mouse carotene-9′,10′-oxygenase (BCDO2 also called BCO2, details of the function of this carotenoid-substrate enzyme are described in Section 2.2.3 and Section 2.2.6 ) is a functionally palmitoylated enzyme that, upon binding to xanthophylls in the mitochondria, can be translocated into the nucleus via depalmitoylation. Once in the nucleus, it may bind to AREs, possibly in association with other transcription factors such as Nrf2, and then regulate downstream gene expression [ 103 ]. It has been reported that mice with whole-body knockout of BCDO2 function developed metabolic dysfunction derived from the peripheral and hypothalamus, even when fed a diet thought to be free of carotenoids.…”

“…In relation to AX, the effect of BCDO2-generated AX metabolites should be considered in the future, because it has only been studied in toxicological aspects, such as CYP induction in rats [ 125 ]. Perhaps independently of these features, BCDO2 itself probably functions as an anti-inflammatory factor through the modulation of several signaling pathways and gene expression [ 103 , 104 , 105 , 106 , 236 , 237 ].…”

In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro)

“…Xanthophylls have multi-focal activity. Among others, their antibacterial [11], antibiofilm [12], antioxidant [13,14], anti-inflammatory [13,15] and anticancer [16] activities have been described. The latest publications indicate that xanthophylls may also have a protective effect in the course of COVID-19 [17,18].…”