Expression and characterization of CYP4V2 as a fatty acid omega-hydroxylase.
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.
Nakano
Mariko
M
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA.
Kelly
Edward J
EJ
Rettie
Allan E
AE
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007908:Lens, Crystalline / Q000201:enzymology / Q000473:pathology; D008861:Microsomes / Q000201:enzymology; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D012162:Retinal Degeneration / Q000201:enzymology / Q000235:genetics; D018411:Spodoptera / Q000166:cytology / Q000201:enzymology / Q000235:genetics
D000578:Amidines; D065607:Cytochrome P-450 Enzyme Inhibitors; C000708209:HET0016; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C505357:CYP4V2 protein, human; D000072470:Cytochrome P450 Family 4; D042926:Cytochrome P-450 CYP4A