Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic.
Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic.
复制标题
DOI：
10.1016/j.jsbmb.2016.02.002
复制
发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Auchus RJ
中科院分区：
文献类型：
--
作者：
Auchus RJ
类固醇17-羟基酶17，20-裂解酶(细胞色素P450c17，P450 17A1，CYP17A1)催化两个主要反应：类固醇17-羟基化和17，20-裂解酶反应。同源的CYP17A1基因最严重的突变会导致所有活性丧失，并导致17-羟基酶/17，20-裂解酶联合缺乏症(17OHD)，这是一种生化表型，通过使用强大的CYP17A1抑制剂醋酸阿比特龙处理而复制。17OHD患者的肾上腺合成11-脱氧皮质酮(DOC)和皮质酮，但不合成19-碳类固醇，与啮齿动物肾上腺相似，DOC可引起高血压和低钾血症。17，20-裂解酶活性的丧失阻碍了性类固醇的合成，并导致性婴儿症。罕见的CYP17A1错义突变最大限度地破坏了17-羟基酶的活性，但会导致孤立的17，20-裂解酶缺乏症(ILD)，编码所需辅因子蛋白细胞色素P450氧化还原酶的POR基因突变会导致从ILD到17OHD的一系列疾病，并伴有21-羟基酶和芳香酶缺乏症，有时包括骨骼畸形。编码第二辅因子蛋白细胞色素b5的CyB5A基因突变也选择性地破坏17，20-裂解酶的活性，并导致最纯粹的ILD。在细胞色素P17A1的生物化学背景下，这些疾病的临床表现是最好的理解。
Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b5 also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations of these conditions are best understood in the context of the biochemistry of CYP17A1.