Structural basis for androgen specificity and oestrogen synthesis in human aromatase.
Structural basis for androgen specificity and oestrogen synthesis in human aromatase.
复制标题
DOI：
10.1038/nature07614
复制
发表时间：
2009-01-08
期刊：
影响因子：
64.8
通讯作者：
Pangborn, Walter
中科院分区：
文献类型：
--
作者：
Ghosh, Debashis;Griswold, Jennifer;Erman, Mary;Pangborn, Walter
芳香酶细胞色素P450是脊椎动物中唯一已知的能催化雄激素合成所有雌激素的酶。芳香化酶抑制剂因此成为雌激素依赖性乳腺癌的一线治疗方法。芳香化酶将雄烯二酮、睾酮和16α-羟睾酮分别转化为雌二醇、17β-雌二醇和17β，16α-雌二醇，每一步需要1 mol O2和1 mol NADPH，并与其氧化还原伙伴细胞色素P450还原酶偶联。前两个步骤是c19 -甲基羟基化，第三个步骤是芳香化酶特有的甾体a环的芳构化。尽管大多数p450不是高度的底物选择性，但它是雄激素特异性的标志，将芳香化酶区分开来。这种内质网膜酶的结构几十年来一直不为人知，阻碍了对其生化机制的阐明。本文介绍了人类胎盘芳香酶的晶体结构，这是迄今为止唯一的天然哺乳动物，全长P450和激素生物合成途径中的P450结晶。与许多代谢药物和外源药物的微粒体p450的活性位点不同，芳香化酶具有雄激素特异性的间隙，可以紧密结合雄烯二酮分子。疏水残基和极性残基巧妙地补充了类固醇骨架。重要催化残基的位置揭示了反应机理。疏水氨基末端区域和催化裂口的相对并置说明了为什么亲脂底物进入活性位点需要膜锚定。该酶雄激素特异性的分子基础和独特的催化机制可用于开发下一代芳香酶抑制剂。
Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a front-line therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme’s androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.
登录
查看更多内容
DOI：
10.1016/0960-0760(93)90241-n
发表时间：
1993-03-01
影响因子：
4.1
作者：
AKHTAR, M;NJAR, VCO;WRIGHT, JN
通讯作者：
WRIGHT, JN
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
GRAHAMLORENCE, S;AMARNEH, B;SIMPSON, ER
通讯作者：
SIMPSON, ER
DOI：
10.1046/j.1432-1033.2001.01886.x
发表时间：
2001-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Kao, YC;Korzekwa, KR;Chen, S
通讯作者：
Chen, S
影响因子：
4.1
作者：
AKHTAR, M;CALDER, MR;WRIGHT, JN
通讯作者：
WRIGHT, JN