Identifying androsterone (ADT) as a cognate substrate for human dehydroepiandrosterone sulfotransferase (DHEA-ST) important for steroid homeostasis - Structure of the enzyme-ADT complex
Identifying androsterone (ADT) as a cognate substrate for human dehydroepiandrosterone sulfotransferase (DHEA-ST) important for steroid homeostasis - Structure of the enzyme-ADT complex
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DOI：
10.1074/jbc.m310446200
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发表时间：
2004-01-23
影响因子：
4.8
通讯作者：
Lin, SX
中科院分区：
文献类型：
--
作者：
Chang, HJ;Shi, R;Lin, SX
在类固醇生物合成中，肾上腺中的人脱氢表雄酮磺基转移酶（DHEA-ST）已被报道催化磺酸基从3 '-磷酸腺苷-5'-磷酸硫酸酯转移到脱氢表雄酮（DHEA）。DHEA及其硫酸盐作为类固醇前体发挥作用;然而，该酶在雄激素催化剂中的作用知之甚少。硫酸雄酮是临床上公认的尿中发现的主要雄激素代谢产物之一。在这里，它表明，这种酶识别雄甾酮（ADT）作为同源底物具有相似的动力学，但2倍的特异性和更强的底物抑制比DHEA。已在2.7埃分辨率下解析了与ADT复合的人DHEA-ST的结构，证实了ADT识别。结构分析表明，ADT的结合模式不同于DHEA，尽管ADT和DHEA二元复合物之间的整体结构相似。我们的研究结果表明，这种人类酶是ADT磺基转移酶以及DHEA磺基转移酶，这意味着肾上腺和肝脏的类固醇体内平衡的重要作用。
In steroid biosynthesis, human dehydroepiandrosterone sulfotransferase (DHEA-ST) in the adrenals has been reported to catalyze the transfer of the sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate to dehydroepiandrosterone (DHEA). DHEA and its sulfate play roles as steroid precursors; however, the role of the enzyme in the catabolism of androgens is poorly understood. Androsterone sulfate is clinically recognized as one of the major androgen metabolites found in urine. Here it is demonstrated that this enzyme recognizes androsterone (ADT) as a cognate substrate with similar kinetics but a 2-fold specificity and stronger substrate inhibition than DHEA. The structure of human DHEA-ST in complex with ADT has been solved at 2.7 Angstrom resolution, confirming ADT recognition. Structural analysis has revealed the binding mode of ADT differs from that of DHEA, despite the similarity of the overall structure between the ADT and the DHEA binary complexes. Our results identify that this human enzyme is an ADT sulfotransferase as well as a DHEA sulfotransferase, implying an important role in steroid homeostasis for the adrenals and liver.