Control of androgen biosynthesis in the human through the interaction of Arg347 and Arg358 of CYP17 with cytochrome b5
Control of androgen biosynthesis in the human through the interaction of Arg347 and Arg358 of CYP17 with cytochrome b5
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DOI：
10.1042/bj3320293
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发表时间：
1998-06-01
影响因子：
4.1
通讯作者：
Akhtar, M
中科院分区：
文献类型：
--
作者：
Lee-Robichaud, P;Akhtar, ME;Akhtar, M
人CYP 17的裂解酶活性（17 α-羟化酶-17，20-裂解酶，也称为P-450 c17或P-450（17 α））在很大程度上依赖于细胞色素B的存在（5），这种作用被认为具有重要的调节作用[Lee-Robichaud，Wright，Akhtar and Akhtar（1995）Biochem.J.308，901-908]。通过对人CYP 17的选定碱性残基进行定点诱变，进一步研究了这方面的问题。对纯化的突变蛋白进行详细的动力学分析。发现Lys（83）、Arg（347）和Arg（358）的突变产生了对细胞色素B（5）的反应性缺陷的蛋白质，并且在患有生殖器模糊的男性患者中发现的两种精氨酸突变体（Arg（347）右箭头His和Arg（358）右箭头Gln）的影响最显著。这些残基介导细胞色素B（5）和CYP 17之间的蛋白质-蛋白质相互作用，从而“唤醒”雄激素形成所需酶的裂解酶活性。
The lyase activity of human CYP17 (17alpha-hydroxylase-17,20-lyase also P-450c17 or P-450(17alpha)) is greatly dependent on the presence of cytochrome b(5), and this effect has been ascribed an important regulatory role [Lee-Robichaud, Wright, Akhtar and Akhtar (1995) Biochem. J. 308, 901-908]. This facet was further investigated by site-directed mutagenesis of selected basic residues of human CYP17. The purified mutant proteins were subjected to detailed kinetic analysis. It was found that the mutation of Lys(83), Arg(347), and Arg(358) produced proteins that were deficient in their responsiveness to cytochrome b(5), and the effect was most pronounced for the two arginine mutants (Arg(347) right-arrow His and Arg(358) right-arrow Gln) which have been found in male patients suffering from genital ambiguity. These residues are invoked to mediate protein-protein interaction between cytochrome b(5) and CYP17, which 'awakens' the lyase activity of the enzyme required for androgen formation.