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Drug Metab Dispos. 2009 Nov;37(11):2119-22. doi: 10.1124/dmd.109.028530. Epub 2009 Aug 6.

Expression and characterization of CYP4V2 as a fatty acid omega-hydroxylase.

Author information

1
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA.

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 omega-hydroxylases that function together with mitochondrial and peroxisomal beta-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 omega-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 omega-hydroxylase specificity. Consequently, defective omega-oxidation of ocular fatty acids/lipids secondary to mutations in the CYP4V2 gene appears to be a plausible mechanism underlying Bietti's crystalline dystrophy.

PMID:
19661213
PMCID:
PMC2774980
DOI:
10.1124/dmd.109.028530
[Indexed for MEDLINE]
Free PMC Article

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