CYP4V2 in Bietti's Crystalline Dystrophy: Ocular Localization, Metabolism of ω-3-Polyunsaturated Fatty Acids, and Functional Deficit of the p.H331P Variant

Nakano, Mariko; Kelly, Edward J.; Wiek, Constanze; Hanenberg, Helmut; Rettie, Allan E.

doi:10.1124/mol.112.080085

Cited by 94 publications

(109 citation statements)

References 39 publications

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“…50 Further to the development of a selective polyclonal antibody against recombinant CYP4V2, the immunocytochemical signal of recombinant CYP4V2 protein was localized in the endoplasmic reticulum of human RPE cell line ARPE-19. 49 Moreover, immunohistochemical signal of the CYP4V2 protein was observed in the RPE cells of human retina. 49 Weak staining was also observed in the ganglion cells and internal and external nuclear layers in the retina and moderate reactivity in corneal epithelial cells.…”

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 98%

“…49 Moreover, immunohistochemical signal of the CYP4V2 protein was observed in the RPE cells of human retina. 49 Weak staining was also observed in the ganglion cells and internal and external nuclear layers in the retina and moderate reactivity in corneal epithelial cells. 49 Gene expression analysis demonstrated that CYP4V2 is the dominantly expressed cytochrome P450 gene in ARPE-19 cells, followed by CYP1B1.…”

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 98%

“…CYP4V2 exhibited ω-hydroxylase activity toward eicosapentaenoic acid (C20:5) and DHA, and the rates of ω-hydroxylation were similar to CYP4F2, an established hepatic PUFA hydroxylase. [48][49][50] Because DHA is a major constituent of ocular membranes, the CYP4V2 protein is likely to be localized in the eye. 50 Further to the development of a selective polyclonal antibody against recombinant CYP4V2, the immunocytochemical signal of recombinant CYP4V2 protein was localized in the endoplasmic reticulum of human RPE cell line ARPE-19.…”

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 99%

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Genetics of Bietti Crystalline Dystrophy

Ng¹,

Lai²,

Ng³

et al. 2016

Asia-Pacific Journal of Ophthalmology

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Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy.

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Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 98%

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 98%

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 99%

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Genetics of Bietti Crystalline Dystrophy

Ng¹,

Lai²,

Ng³

et al. 2016

Asia-Pacific Journal of Ophthalmology

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“…P450s 4B1, 4V2, and 4X1 have orthologues in other vertebrate species, whereas the P450 4A and 4F subfamilies exhibit paralogues with differences in the number of genes for these two subfamilies in other species (1,2). Although these enzymes often exhibit overlapping substrate specificities, genetic association studies link the -hydroxylase CYP4V2 to the Bietti's crystalline dystrophy, which is characterized by ocular lipid deposits (7,8), suggesting a key role for CYP4V2 in the removal of excess lipids in ocular tissues. Furthermore, CYP4F22 genetic variants are associated with lamellar ichthyosis, which reflects deficiencies in the water permeability barrier of skin (9).…”

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confidence: 99%

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

Hsu

Baer

Rettie

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeP450 family 4 fatty acid -hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for -hydroxylation. The structure indicated that octane is bound in a narrow active-site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for -hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized Glu-310 contributes to substrate positioning. The preference for -hydroxylation was decreased in an E310A mutant having a shorter side chain, but the overall rates of metabolism were retained. E310D and E310Q substitutions having longer side chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane -hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for -hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for -hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of unactivated primary C-H bonds.Cytochrome P450 family 4 fatty acid -hydroxylases are heme-containing monooxygenases that provide pathways for the reduction of potentially toxic non-esterified fatty acids and for the elimination of excess nutritive and non-nutritive lipids by catalyzing the addition of oxygen to a C-H bond of the terminal -carbon of fatty acids (1, 2). The resulting -alcohols are generally oxidized further to produce dicarboxylic acids, but they also may be transformed to glucuronides or esterified to glycerolipids. Urinary dicarboxylic fatty acids are elevated in humans by fasting or in uncontrolled diabetes, which are conditions where adipocyte lipolysis increases the availability of non-esterified fatty acids to fuel metabolism (3). It is estimated that roughly 15% of fatty acids undergo -hydroxylation during peak periods of fatty acid catabolism (4), whereas this fraction is much smaller under conditions where concentrations of nonesterified fatty acids are low (5). Collectively, these enzymes provide pathways for the metabolic clearance of branched chain fatty acids, eicosanoids, and xenobiotic substrates such as dietary phytanic acid, drugs, toxins, and vitamins E and K (1, 2, 6).Similar to other P450 2 gene families encoding multipurpose enzymes for the elimination of xenobiotic compounds, family 4 exhibits genetic diversi...

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“…6 Consistent with this, abnormalities in ω3-PUFAs and their metabolism have been demonstrated in patients with BCD. 4,7,8 The retinal findings and systemic lipid abnormalities have been recapitulated in a knockout mouse model. 9 Before this study, 73 mutations in CYP4V2 have been described in the literature and clinical databases.…”

Section: Introductionmentioning

confidence: 99%

Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy

Jiao

Jin

et al. 2017

Eur J Hum Genet

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To identify known and novel CYP4V2 mutations in patients with Bietti crystalline cornea (BCD), expand the spectrum of CYP4V2 mutations, and characterize the population history of the c.802-8_810del17insGC mutation common in Asian populations, genomic DNA was isolated from peripheral blood samples from 58 unrelated patients with clinical diagnoses of BCD. Exons and flanking intronic regions of the CYP4V2 gene were dideoxy DNA sequenced. Nonpathogenic polymorphisms were excluded and known mutations were identified by sequencing 192 unaffected individuals from similar ethnic backgrounds and examination of online databases. The age of the c.802-8_810del17insGC mutation was estimated using three independent approaches. A total of 28 CYP4V2 mutations, 9 of which were novel, were detected in the 58 patients with BCD. These included 19 missense, 4 nonsense, 2 deletion, 2 splice site, and 1 insertion-deletion mutations. Two missense variants of uncertain significance were also detected. The age of the c.802-8_810del17insGC mutation was estimated to be 1040-8200 generations in the Chinese and 300-1100 generations in the Japanese populations. These results expand the mutation spectrum of CYP4V2, and provide insight into the origin of the c.802-8_810del17insGC mutation in the Chinese population and its transmission to the Japanese population.

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CYP4V2 in Bietti's Crystalline Dystrophy: Ocular Localization, Metabolism of ω-3-Polyunsaturated Fatty Acids, and Functional Deficit of the p.H331P Variant

Cited by 94 publications

References 39 publications

Genetics of Bietti Crystalline Dystrophy

Genetics of Bietti Crystalline Dystrophy

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy

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