Abstract
Bietti's crystalline dystrophy is an ocular disease that is strongly associated with polymorphisms in the CYP4V2 gene. CYP4 enzymes are typically microsomal fatty acid ω-hydroxylases that function together with mitochondrial and peroxisomal β-oxidation enzymes to degrade cellular lipids. Indeed, ocular and peripheral cells cultured from patients with Bietti's have been reported to exhibit abnormal lipid metabolism. However, CYP4V2 possesses low sequence homology to other members of the CYP4 family. Therefore, we cloned and expressed CYP4V2 and analyzed the functional characteristics of this new cytochrome P450 enzyme. We find that CYP4V2 is a selective ω-hydroxylase of saturated, medium-chain fatty acids with relatively high catalytic efficiency toward myristic acid. Moreover, N-hydroxy-N′-(4-n-butyl-2-methylphenyl formamidine) (HET0016) is a nanomolar inhibitor of the enzyme. Therefore, CYP4V2 exhibits catalytic functions typical of a human CYP4 enzyme, but with a distinctive chain-length selectivity coupled with high ω-hydroxylase specificity. Consequently, defective ω-oxidation of ocular fatty acids/lipids secondary to mutations in the CYP4V2 gene appears to be a plausible mechanism underlying Bietti's crystalline dystrophy.
- P450, cytochrome P450
- BCD, Bietti's corneoretinal crystalline dystrophy
- HET0016, N-hydroxy-N′-(4-n-butyl-2-methylphenyl formamidine)
- BSTFA, N,O-bis(trimethylsilyl)trifluoroacetate
- GC-MS, gas chromatography-mass spectrometry
- TMS, trimethylsyl.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM49054].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028530
- Received May 19, 2009.
- Accepted August 3, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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