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Inactivity of Human Β,Β-Carotene-9′,10′-Dioxygenase (BCO2) Underlies Retinal Accumulation of the Human Macular Carotenoid Pigment

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Inactivity of Human Β,Β-Carotene-9′,10′-Dioxygenase (BCO2) Underlies Retinal Accumulation of the Human Macular Carotenoid Pigment Inactivity of human β,β-carotene-9′,10′-dioxygenase (BCO2) underlies retinal accumulation of the human macular carotenoid pigment Binxing Lia,1, Preejith P. Vachalia,1, Aruna Gorusupudia, Zhengqing Shena, Hassan Sharifzadeha, Brian M. Bescha, Kelly Nelsona, Madeleine M. Horvatha, Jeanne M. Fredericka, Wolfgang Baehra,b,c, and Paul S. Bernsteina,2 aDepartment of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and bDepartment of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132; and cDepartment of Biology, University of Utah, Salt Lake City, UT 84112 Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved June 6, 2014 (received for review February 9, 2014) The macula of the primate retina uniquely concentrates high amounts humans express a zeaxanthin-binding protein, the pi isoform of of the xanthophyll carotenoids lutein, zeaxanthin, and meso- glutathione S-transferase (GSTP1), abundantly in the retina, zeaxanthin, but the underlying biochemical mechanisms for this yet only the human retina naturally contains zeaxanthin and spatial- and species-specific localization have not been fully elu- meso-zeaxanthin (11, 12). Thus, other biochemical mechanisms cidated. For example, despite abundant retinal levels in mice and underlying accumulation of the human macular pigment need to primates of a binding protein for zeaxanthin and meso-zeaxanthin, be considered. the pi isoform of glutathione S-transferase (GSTP1), only human and β,β-Carotene-9′,10′-dioxygenase (BCO2, also known as BCDO2) monkey retinas naturally contain detectable levels of these ca- is a xanthophyll carotenoid cleavage enzyme which can cleave rotenoids. We therefore investigated whether or not differences in carotenoids in many animals eccentrically at the 9–10 or 9′-10′ expression, localization, and activity between mouse and primate ca- carbon–carbon double bonds into C13- and C27-apocarotenoids, or rotenoid metabolic enzymes could account for this species-specific further into C14-dialdehyde (13, 14). Its physiological function is difference in retinal accumulation. We focused on β,β-carotene- supported by genetic evidence from several species. A nonsense 9′,10′-dioxygenase (BCO2, also known as BCDO2), the only known mutation in the sheep BCO2 gene that introduces a stop codon mammalian xanthophyll cleavage enzyme. RT-PCR, Western blot at amino acid 66 of the 575-aa full-length protein is strongly analysis, and immunohistochemistry (IHC) confirmed that BCO2 is associated with a yellow fat phenotype due to the high amount of expressed in both mouse and primate retinas. Cotransfection of lutein that deposits in tissue (15). Cis-acting and tissue-specific expression plasmids of human or mouse BCO2 into Escherichia regulatory mutations that inhibit the expression of BCO2 in do- coli strains engineered to produce zeaxanthin demonstrated mestic chickens can cause them to have yellow skin secondary to that only mouse BCO2 is an active zeaxanthin cleavage enzyme. carotenoid accumulation (16). Genetic variations in the BCO2 Surface plasmon resonance (SPR) binding studies showed that the gene have been reported to increase carotenoid levels in bovine binding affinities between human BCO2 and lutein, zeaxanthin, adipose tissue and milk (17). In vitro biochemical studies have and meso-zeaxanthin are 10- to 40-fold weaker than those for also demonstrated that ferret BCO2 can cleave lutein and mouse BCO2, implying that ineffective capture of carotenoids by hu- zeaxanthin (13). man BCO2 prevents cleavage of xanthophyll carotenoids. Moreover, BCO2, β,β-carotene-15,15′-monooxygenase (BCO1), and retinal BCO2 knockout mice, unlike WT mice, accumulate zeaxanthin in pigment epithelium-specific 65 kDa protein (RPE65) are members their retinas. Our results provide a novel explanation for how of the polyene oxygenase gene family. BCO1, which is also known primates uniquely concentrate xanthophyll carotenoids at high as BCMO1, cleaves β-carotene symmetrically at the 15–15′ posi- levels in retinal tissue. tion to yield two molecules of retinal, the key pigment in the visual cycle, and it is inactive with xanthophyll (oxygenated) carotenoids he macular pigment of the human retina consists of the such as lutein and zeaxanthin (18, 19). RPE65, an essential en- Txanthophyll carotenoids, lutein, zeaxanthin, and their me- zyme in the visual cycle, participates in the conversion of all-trans- tabolite, meso-zeaxanthin (1–3). Macular pigments are highly retinyl palmitate to 11-cis-retinol, and various mutations are concentrated in the foveal area of the human retina. Their highest concentration can reach 1 mM, making the macula Significance a visible yellow spot at the center of the human retina. These xanthophylls are known to play antioxidant and light-screening Among mammals, only primates can accumulate high levels of BIOCHEMISTRY roles in nature (4–6). Clinical studies have shown that lutein and xanthophyll carotenoids in their retinas. We discovered that, zeaxanthin supplementation can reduce the risk of age-related unlike most other mammals, the major xanthophyll cleavage macular degeneration (AMD), a leading cause of blindness in enzyme β,β-carotene-9′,10′-dioxygenase (BCO2) is inactive in the developed world (4, 7, 8). Recently, the Age-Related Eye humans, explaining the unique accumulation of lutein, zeax- Disease Study 2 (AREDS2) showed that daily oral supplemen- anthin, and meso-zeaxanthin in primate macula. We confirmed tation with 10 mg lutein and 2 mg zeaxanthin was associated with this discovery by demonstrating that BCO2 knockout mice ac- 10–18% reduced progression to advanced AMD over the 5-y cumulate zeaxanthin in their retinas. study relative to original Age-Related Eye Disease Study (AREDS) formulations without lutein and zeaxanthin, and the Author contributions: B.L., W.B., and P.S.B. designed research; B.L., P.P.V., A.G., Z.S., H.S., authors recommended adding lutein and zeaxanthin to re- B.M.B., K.N., M.M.H., and J.M.F. performed research; B.L., P.P.V., W.B., and P.S.B. analyzed place β-carotene in the formulation for safety and efficacy data; and B.L., W.B., and P.S.B. wrote the paper. reasons (9, 10). The authors declare no conflict of interest. The spatially and chemically specific accumulation of high This article is a PNAS Direct Submission. concentrations of xanthophylls in the retina is a unique feature of 1B.L. and P.P.V. contributed equally to this work. the primate retina relative to other mammals, but the bio- 2To whom correspondence should be addressed. E-mail: [email protected]. chemical basis for this high degree of specificity is unclear. High- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. affinity binding proteins might drive this process. Mice and 1073/pnas.1402526111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1402526111 PNAS | July 15, 2014 | vol. 111 | no. 28 | 10173–10178 Downloaded by guest on October 2, 2021 it suggests that the enzyme is a functional enzyme. The yellow color of zeaxanthin was faded in the bacteria transfected with mouse BCO2 plasmids (Fig. 3A), demonstrating that mouse BCO2 can cleave zeaxanthin. Human BCO2 isoform a (human BCO2a) failed to cleave zeaxanthin, retaining the yellow color. The cleavage products of each assay were then analyzed by HPLC (Fig. 3B). Chromatograms of the human BCO2 experiments were identical to those of the control experiments, consistent with absence of cleavage activity. In the chromatogram of the mouse BCO2 ex- periment, the elution peak of zeaxanthin almost disappeared, whereas a new peak appeared at 14.22 min whose diode-array spectrum was consistent with C14-dialdehyde (also known as rosafluene dialdehyde; Fig. 3B, Inset), a previously reported Fig. 1. Expression of BCO2 in the human retina and localization in monkey major cleavage product of zeaxanthin by BCO2 (14). These retina. (A) Western blot of human retina lysates probed with anti-BCO2. The experiments demonstrate that human retinal BCO2 is an in- ∼ BCO2 polypeptide has a mobility of 65 kDa [calculated molecular weight active enzyme, whereas mouse BCO2 is an active carotenoid (MW) = 65,674 for the BCO2a isoform]. (B) RT-PCR with human retina cDNA and isoform-specific oligonucleotide primers. Human BCO2 isoform a (1) but cleavage enzyme. not isoforms b (2) or c (3) could be identified. (C) IHC of perfusion-fixed monkey retina cryosection probed with antibody directed against BCO2 Protein Sequence and Structure Analysis. To explain the functional (green). Propidium iodide (red) permits visualization of nuclear layers. GCL, difference between human BCO2 and mouse BCO2, we ana- ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS, lyzed the amino acid sequences of human BCO2a and mouse inner segment layer; ONL, outer nuclear layer; OPL, outer plexiform layer. BCO2. Sequence alignments (Fig. 4, Upper) show that the major Scale bar: 20 μm. difference between human BCO2a enzyme and mouse BCO2 is the presence of 4 aa residues, GKAA, in human BCO2 (Fig. 4), suggesting the loss of an alternate splice site in the human gene. associated with Leber congenital amaurosis type 2 and retinitis – An NCBI protein database search revealed that this GKAA in- pigmentosa (18, 20 22). BCO2 may also play important roles in sertion is apparently unique to primates and is absent in cows, ocular tissues, but a physiological function has not been estab- sheep, rats, mice, and ferrets. GKAA is also absent in human and lished. Based on the fact that high amounts of lutein and zeax- mouse RPE65 that can actively cleave all-trans-retinyl esters. anthin exist in the human macula, we hypothesized that either Inspecting the human and mouse BCO2 genes reveals that human BCO2 is not expressed in human retina or it is an inactive GKAA represents an extension of human BCO2 exon 3 caused carotenoid cleavage enzyme. In this study, we tested these pro- by use of an alternate donor splice site (Fig.
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