Probing the frontiers of glycoprotein synthesis: the fully elaborated β-subunit of the human follicle-stimulating hormone.
Probing the frontiers of glycoprotein synthesis: the fully elaborated β-subunit of the human follicle-stimulating hormone.
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DOI：
10.1002/anie.201107482
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发表时间：
2012-01-23
影响因子：
16.6
通讯作者：
Danishefsky, Samuel J.
中科院分区：
文献类型：
--
作者：
Nagorny, Pavel;Sane, Neeraj;Fasching, Bernhard;Aussedat, Baptiste;Danishefsky, Samuel J.
人促卵泡激素（hFSH）属于负责维持基本生殖过程（促性腺激素）的激素家族。[1]FSH在垂体前叶产生，FSH与其受体的结合刺激女性卵泡的成熟和雌激素的产生，并维持男性的精子发生。[2]因此，FSH在临床上用于治疗与不孕症相关的无排卵性疾病。[3]给药通常是皮下注射的形式，通常每天一次，持续很长一段时间。这种治疗的副作用包括过敏反应和恶心，情绪波动和疲劳。[4]目前，FSH主要来自重组技术，特别是来自中国人卵巢（CHO）细胞。[5]如此获得的物质是激素糖型的复杂混合物，即维斯于肽主链上的碳水化合物高度异质。[6]在正常成年人中，FSH受体（FSH-R）仅在女性的卵巢颗粒细胞和男性的睾丸支持细胞上表达。然而，在最近的发现中，发现FSH-R在乳腺、前列腺、结肠、胰腺、肾、胃、睾丸和卵巢的肿瘤周围的内皮细胞上普遍表达。[7]早期的小鼠研究表明，FSH对肿瘤生长的影响至少与表皮生长因子（EGF）一样有效。[8]尽管这种效应存在浓度依赖性，但目前由于缺乏FSH的同质形式，对各种糖型的相对作用的有趣研究受到阻碍。在结构上，FSH是一种由两个非共价结合的亚基（α和β）组成的异源二聚体糖蛋白（1，图1）。[9]每个亚基包含两个N-连接的寡糖-α-亚基位于Asn 52和Asn 78，β-亚基位于Asn 7和Asn 24，它们通过肽骨架的共翻译修饰掺入粗面内质网（RER）。寡糖的结构在靶受体的正确折叠、亚基组装、分泌和活化以及最终分子的代谢命运中起着至关重要的作用。[10]显然，获得FSH的同质糖型的方法对于建立结构-
The human follicle-stimulating hormone (hFSH) belongs to a family of hormones responsible for the maintenance of essential reproductive processes (gonadotropins).[1] FSH is produced in the anterior pituitary, and the binding of FSH to its receptor stimulates the maturation of follicles and the production of estrogen in females, and maintains spermatogenesis in males.[2] Consequently, FSH is clinically used in the treatment of anovulatory disorders associated with infertility.[3] Administration is usually in the form of subcutaneous injections, often once a day, over prolonged periods of time. Side effects of this treatment range from allergic reactions and nausea, to mood swings and fatigue.[4] Presently, FSH is mainly derived from recombinant technologies, specifically, from Chinese Hamster Ovary (CHO) cells.[5] The material so obtained is a complex mixture of hormone glycoforms, ie highly heterogeneous vis-à-vis the carbohydrates on the peptide backbone.[6] In normal adult humans, the FSH receptor (FSH-R) is expressed only on the ovarian granulosa cells of females and the testicular Sertoli cells of males. However, in a recent discovery it was found that the FSH-R is ubiquitously expressed on the endothelial cells of the peripheries of the tumors of the breast, prostrate, colon, pancreas, kidney, stomach, testis and ovary.[7] Earlier studies in mice have indicated that the effect of FSH on the growth of tumors is at least as potent as that of epidermal growth factor (EGF).[8] Although there was a concentration dependency of this effect, what might be an interesting study of the relative roles of the various glycoforms is presently stymied by the unavailability of homogeneous forms of FSH.Structurally, FSH is a heterodimeric glycoprotein composed of two non-covalently associated subunits (α and β)(1, Figure 1).[9] Each of the subunits contains two N-linked oligosaccharides—the α-subunit at Asn52 and Asn78, and the β-subunit at Asn7 and Asn24, which are incorporated in the rough endoplasmic reticulum (RER) through co-translational modifications of the peptide backbone. The structures of the oligosaccharides play a crucial role in the proper folding, subunit assembly, secretion, and activation of the target receptor and, ultimately, the metabolic fate of the molecule.[10] Clearly, a method for gaining access to homogeneous glycoforms of FSH would be highly desirable for establishing a structure-
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影响因子：
56.9
作者：
DAWSON, PE;MUIR, TW;KENT, SBH
通讯作者：
KENT, SBH
影响因子：
16.6
作者：
Haase, Christian;Rohde, Heike;Seitz, Oliver
通讯作者：
Seitz, Oliver
影响因子：
3.2
作者：
Harpaz, Ziv;Siman, Peter;Brik, Ashraf
通讯作者：
Brik, Ashraf
影响因子：
4.3
作者：
Danishefsky, SJ;Hu, S;Seeberger, PH
通讯作者：
Seeberger, PH
影响因子：
16.6
作者：
Bang, D;Makhatadze, GI;Kent, SB
通讯作者：
Kent, SB