dehydroepiandrosterone sulfate | 129509-11-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: dehydroepiandrosterone sulfate
• 英文别名: [3H]dehydroepiandrosterone sulfate；[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-yl] sulfate
• CAS: 129509-11-1
• 化学式: C₁₉H₂₇O₅S
• 分子量: 367.486
• InChiKey: CZWCKYRVOZZJNM-USOAJAOKSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  91.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  dehydroepiandrosterone sulfate 在 sodium tetrahydroborate 作用下， 以 水 为溶剂， 反应 0.5h， 生成 androst-5-ene-3β,17β-diol 3-ammonium sulphate
  参考文献：
  名称：

  Kirk, David N.; Rajagopalan, Maruthiandan S., Journal of the Chemical Society. Perkin transactions I, 1987, p. 1339 - 1342

  摘要：

  DOI：
• 作为产物：
  描述：

  PAPS 、 去氢表雄酮 生成 dehydroepiandrosterone sulfate 、 Adenosine 3',5'-bismonophosphate(4-) 、 氢(+1)阳离子
  参考文献：
  名称：

  Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies

  摘要：

  SULT2A1催化脱氢表雄酮（DHEA）和其他类固醇的硫酸盐结合。作为药物遗传学研究的一个步骤，我们使用60个非裔美国人的DNA样本和60个高加索美国人的DNA样本对SULT2A1进行了“重新测序”。我们对所有外显子、剪接连接点以及位于转录起始位点5个碱基对处的大约370个碱基对进行了测序。我们观察到15个单核苷酸多态性（SNP），包括三个非同义编码SNP（cSNP），它们只存在于非裔美国人的DNA中。连锁分析显示，其中两个非同义cSNP紧密连锁。我们为观察到的所有非同义cSNP创建了表达构建体，包括一个包含两个连锁cSNP的“双变异”构建体，这些构建体在COS-1细胞中表达。在四种变异同工酶中，有三种的SULT2A1活性显著降低。虽然重组同工酶的Km值也各不相同，但免疫反应蛋白水平降低似乎是导致活性降低的主要机制。此外，最常见的非同义cSNP破坏了SULT2A1中与二聚体化相关的部分，这种变异同工酶在凝胶过滤色谱法中表现为单体而不是二聚体。这些观察结果表明，SULT2A1的常见遗传多态性

  DOI：

  10.1038/sj.tpj.6500089

文献信息

• Functional characterization of seven single-nucleotide polymorphisms of the steroid sulfatase gene found in a Japanese population
  作者：Jun Matsumoto、Noritaka Ariyoshi、Itsuko Ishii、Mitsukazu Kitada

  DOI：10.1038/jhg.2013.12

  日期：2013.5

  Steroid sulfatase (STS) is an enzyme that hydrolyzes steroid sulfates such as dehydroepiandrosterone sulfate (DHEA-S) and estrone sulfate. STS has a key role in the synthesis of steroid hormones in placenta and breast cancer cells. Recently, we have identified six novel single-nucleotide polymorphisms (SNPs) and one nonsynonymous SNP (V476M) in the STS gene in a Japanese population. To clarify the effects of SNPs in the 5′-flanking region or 5′ untranslated region on transcriptional activity, a reporter gene assay was conducted. In addition, DHEA-S desulfatase activity of a variant (Met at codon 476)-type enzyme was compared with that of the wild (Wd)-type enzyme in COS-1 cells. The transcriptional activities were significantly decreased (155A) and increased (−2837A and −1588C) in MCF-7 cells. On the other hand, no significant difference was found in expression levels of STS protein or specific activities of DHEA-S desulfation between Wd and the variant enzymes. This is the first report on the effects of various SNPs in the STS gene detected in Japanese healthy subjects.

  类固醇硫酸酯酶（STS）是一种水解类固醇硫酸酯的酶，如硫酸脱氢表雄酮（DHEA-S）和硫酸雌酮。STS在胎盘和乳腺癌细胞中合成类固醇激素的过程中起着关键作用。最近，我们在日本人群中发现了STS基因中的6个新单核苷酸多态性（SNP）和1个非同义SNP（V476M
• Helices F–G Are Important for the Substrate Specificities of CYP3A7
  作者：Nao Torimoto、Itsuko Ishii、Ken-Ichi Toyama、Masayuki Hata、Kanako Tanaka、Hitoshi Shimomura、Hiroyoshi Nakamura、Noritaka Ariyoshi、Shigeru Ohmori、Mitsukazu Kitada

  DOI：10.1124/dmd.106.011304

  日期：2007.3

  CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone (DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16α-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu210 to Glu279 were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16α-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F–G loops.

  CYP3A7是人体CYP3A家族的一员，也是人体胎儿肝脏中P450的主要形式。尽管CYP3A7与CYP3A4的碱基序列几乎相同，但CYP3A7在几种底物的催化偏好方面表现出显著的功能差异，例如脱氢表雄酮（DHEA）或脱氢表雄酮3-硫酸盐（DHEA-3S）。首先，为了弄清CYP3A7和CYP3A4之间差异的原因，我们使用CYP3A4晶体结构构建了CYP3A7的同源模型。由于这两种结构相似，我们构建了四种嵌合酶来确定哪些序列对于表现出CYP3A7的特征很重要。CYP3A7、CYP3A4和CYP3A嵌合酶对DHEA和DHEA-3S 16α-羟基化的动力学分析结果表明，从Leu210到Glu279的氨基酸残基对于表达CYP3A7底物的特异性很重要。该区域位于建模的CYP3A7的F和G螺旋上。此外，为了评估该序列中的哪种氨基酸对于CYP3A7的底物特异性很重要，我们通过定点诱变将CYP3A7突变为CYP3A4。K224T和K244E
• Human Hydroxysteroid Sulfotransferase SULT2B1: Two Enzymes Encoded by a Single Chromosome 19 Gene
  作者：Chengtao Her、Thomas C. Wood、Evan E. Eichler、Harvey W. Mohrenweiser、Louis S. Ramagli、Michael J. Siciliano、Richard M. Weinshilboum

  DOI：10.1006/geno.1998.5518

  日期：1998.11

  have cloned and characterized cDNAs that encode two human hydroxysteroid sulfotransferase (SULT) enzymes, SULT2B1a and SULT2B1b, as well as the single gene that encodes both of these enzymes. The two cDNAs differed at their 5'-termini and had 1050- and 1095-bp open reading frames that encoded 350 and 365 amino acids, respectively. The amino acid sequences encoded by these cDNAs included "signature sequences"

  我们已经克隆和鉴定了编码两个人类羟基甾体磺基转移酶（SULT）酶SULT2B1a和SULT2B1b的cDNA，以及编码这两个酶的单个基因。这两个cDNA的5'末端不同，并具有1050和1095 bp的开放阅读框，分别编码350和365个氨基酸。这些cDNA编码的氨基酸序列包括在所有已知的胞质SULT中保守的“特征序列”。根据氨基酸序列分析，这两个cDNA似乎都是羟基类固醇SULT“家族” SULT2的成员，但在氨基酸序列上与人类中该家族的单个已知成员SULT2A1（也称为DHEA ST）。Northern印迹分析表明存在SULT2B1 mRNA约1。在人胎盘，前列腺和气管中的长度为4 kb，在小肠和肺中的长度为4 kb。两个人SULT2B1 cDNA在COS-1细胞中的表达表明，两种编码蛋白均催化原型羟基甾体SULT底物脱氢表雄酮的硫酸盐化，但均未能催化4-硝基苯酚或17β-雌二醇的硫酸盐
• Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies
  作者：B A Thomae、B W Eckloff、R R Freimuth、E D Wieben、R M Weinshilboum

  DOI：10.1038/sj.tpj.6500089

  日期：2002.1.1

  SULT2A1 catalyzes the sulfate conjugation of dehydroepiandrosterone (DHEA) as well as other steroids. As a step toward pharmacogenetic studies, we have ‘resequenced’ SULT2A1 using 60 DNA samples from African-American and 60 samples from Caucasian-American subjects. All exons, splice junctions and approximately 370 bp located 5′ of the site of transcription initiation were sequenced. We observed 15 single nucleotide polymorphisms (SNPs), including three non-synonymous coding SNPs (cSNPs) that were present only in DNA from African-American subjects. Linkage analysis revealed that two of the nonsynonymous cSNPs were tightly linked. Expression constructs were created for all nonsynonymous cSNPs observed, including a ‘double variant’ construct that included the two linked cSNPs, and those constructs were expressed in COS-1 cells. SULT2A1 activity was significantly decreased for three of the four variant allozymes. Western blot analysis demonstrated that decreased levels of immunoreactive protein appeared to be the major mechanism responsible for decreases in activity, although apparent Km values also varied among the recombinant allozymes. In addition, the most common of the nonsynonymous cSNPs disrupted the portion of SULT2A1 involved with dimerization, and this variant allozyme behaved as a monomer rather than a dimer during gel filtration chromatography. These observations indicate that common genetic polymorphisms for SULT2A1 can result in reductions in levels of both activity and enzyme protein. They also raise the possibility of ethnic-specific pharmacogenetic variation in SULT2A1-catalyzed sulfation of both endogenous and exogenous substrates for this phase II drug-metabolizing enzyme.

  SULT2A1催化脱氢表雄酮（DHEA）和其他类固醇的硫酸盐结合。作为药物遗传学研究的一个步骤，我们使用60个非裔美国人的DNA样本和60个高加索美国人的DNA样本对SULT2A1进行了“重新测序”。我们对所有外显子、剪接连接点以及位于转录起始位点5个碱基对处的大约370个碱基对进行了测序。我们观察到15个单核苷酸多态性（SNP），包括三个非同义编码SNP（cSNP），它们只存在于非裔美国人的DNA中。连锁分析显示，其中两个非同义cSNP紧密连锁。我们为观察到的所有非同义cSNP创建了表达构建体，包括一个包含两个连锁cSNP的“双变异”构建体，这些构建体在COS-1细胞中表达。在四种变异同工酶中，有三种的SULT2A1活性显著降低。虽然重组同工酶的Km值也各不相同，但免疫反应蛋白水平降低似乎是导致活性降低的主要机制。此外，最常见的非同义cSNP破坏了SULT2A1中与二聚体化相关的部分，这种变异同工酶在凝胶过滤色谱法中表现为单体而不是二聚体。这些观察结果表明，SULT2A1的常见遗传多态性
• Structure of Human Estrone Sulfatase Suggests Functional Roles of Membrane Association
  作者：Francisco G. Hernandez-Guzman、Tadayoshi Higashiyama、Walter Pangborn、Yoshio Osawa、Debashis Ghosh

  DOI：10.1074/jbc.m211497200

  日期：2003.6

  Estrone sulfatase (ES; 562 amino acids), one of the key enzymes responsible for maintaining high levels of estrogens in breast tumor cells, is associated with the membrane of the endoplasmic reticulum (ER). The structure of ES, purified from the microsomal fraction of human placentas, has been determined at 2.60-A resolution by x-ray crystallography. This structure shows a domain consisting of two antiparallel alpha-helices that protrude from the roughly spherical molecule, thereby giving the molecule a "mushroom-like" shape. These highly hydrophobic helices, each about 40 A long, are capable of traversing the membrane, thus presumably anchoring the functional domain on the membrane surface facing the ER lumen. The location of the transmembrane domain is such that the opening to the active site, buried deep in a cavity of the "gill" of the "mushroom," rests near the membrane surface, thereby suggesting a role of the lipid bilayer in catalysis. This simple architecture could be a prototype utilized by the ER membrane in dictating the form and the function of ER-resident enzymes.