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  • Title: Importance of successive prolines in the carboxy-terminal region of P450 2C2 and P450 2C14 for the hydroxylase activities.
    Author: Uno T, Imai Y, Nakamura M, Okamoto N, Fukuda T.
    Journal: J Biochem; 1993 Sep; 114(3):363-9. PubMed ID: 8282727.
    Abstract:
    Proline-480 and proline-481 are highly conserved in the P450 2 family. When these successive prolines of P450 2C2 were replaced by Ala-Thr, its activities of laurate (omega-1)-hydroxylation and benzphetamine N-demethylation were lost. On the other hand, the mutated P450 which retained one of the proline residues was 60-100% active in the (omega-1)-hydroxylation and 100-120% active in the N-demethylation. Pro-Pro (480, 481) to Ala-Thr mutated P450 2C14 was also inactive in testosterone 16 alpha-hydroxylation and benzphetamine N-demethylation, the activities of the wild-type P450 2C14. In the carboxyterminal region of the P450 2C subfamily, the sequence of P450 2C2 from residues 469-473 is noticeably different from those of the other members of this subfamily. The Ser-473 to Val mutation of P450 2C2 caused a decrease in the (omega-1)-hydroxylase activity to one-fifth but the N-demethylase activity was not much affected. When the sequence of P450 2C2 from residues 469-473 was replaced by that of P450 2C14 (mutation at four residues), the 16 alpha-hydroxylase and N-demethylase activities were increased by seven- and three-fold, respectively, and the (omega-1)-hydroxylase activity was decreased to one-third. The mutated P450 2C2, in which the carboxy-terminal four residue sequence or the proline cluster adjacent to the amino-terminal membrane-anchor signal sequences was deleted, was not accumulated in yeast cells transformed with plasmids directing the synthesis of such P450s.(ABSTRACT TRUNCATED AT 250 WORDS)
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