Human CYP17 (17α-hydroxylase-17,20-lyase; also cytochrome P450c17 or cytochrome P45017α) catalyses a hydroxylation reaction and another reaction involving the cleavage of a C-C bond (the lyase activity) that is required only for androgen production. Single amino acid mutations in human CYP17, Arg347 → His and Arg358 → Gln, have been reported to result in the loss of the lyase activity and to cause sexual phenotypic changes in 46XY male patients. By using site-directed mutagenesis we show here that another mutation in human CYP17, Arg449 → Ala, for which human variants have yet not been described, also leads to selective lyase deficiency. Furthermore, all the three types of mutants display a loss of responsiveness to cytochrome b5, an interaction that is essential for lyase activity, and hence male sex-hormone biosynthesis. That the defect could be essentially reversed by lysine mutagenesis has led to the conclusion that the cationic charges on all three residues (at the positions of Arg347, Arg358, Arg449) are vital for the functional interaction of CYP17 with cytochrome b5 and that the loss of any one of these cationic charges is catastrophic.
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Research Article|
August 24 1999
Lysine mutagenesis identifies cationic charges of human CYP17 that interact with cytochrome b5 to promote male sex-hormone biosynthesis
Peter LEE-ROBICHAUD;
Peter LEE-ROBICHAUD
1Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
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Monika E. AKHTAR;
Monika E. AKHTAR
1Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
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Muhammad AKHTAR
Muhammad AKHTAR
1
1Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
1To whom correspondence should be addressed (m.akhtar@soton.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 20 1999
Revision Received:
June 01 1999
Accepted:
June 21 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 342 (2): 309–312.
Article history
Received:
April 20 1999
Revision Received:
June 01 1999
Accepted:
June 21 1999
Citation
Peter LEE-ROBICHAUD, Monika E. AKHTAR, Muhammad AKHTAR; Lysine mutagenesis identifies cationic charges of human CYP17 that interact with cytochrome b5 to promote male sex-hormone biosynthesis. Biochem J 1 September 1999; 342 (2): 309–312. doi: https://doi.org/10.1042/bj3420309
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