Cysteamine revisited: repair of arginine to cysteine mutations.
Cysteamine revisited: repair of arginine to cysteine mutations.
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DOI：
10.1007/s10545-017-0060-4
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发表时间：
2017-07
影响因子：
4.2
通讯作者：
Blom HJ
中科院分区：
文献类型：
--
作者：
Gallego-Villar L;Hannibal L;Häberle J;Thöny B;Ben-Omran T;Nasrallah GK;Dewik AN;Kruger WD;Blom HJ
半胱胺是一种内源性来源于辅酶A降解的小氨基硫醇。几十年来，合成半胱胺已被用于治疗胱氨酸病，并且该药物的新用途不断出现。在这篇综述中，我们讨论了半胱胺在细胞内和细胞外的稳态的作用，并侧重于潜在的使用氨基硫醇，以重建的功能的蛋白质窝藏精氨酸（Arg）的半胱氨酸（Cys）突变，通过修复的Cys残基到一个部分，引入一个氨基，如在碱性氨基酸残基赖氨酸和精氨酸。半胱胺已在体外和离体用于四种不同的遗传性疾病，因此提供了氨基硫醇可以修饰Cys残基的“原理证明”。其他氨基硫醇，如巯基乙基胍（MEG）与精氨酸的胍部分的结构更接近的相似性正在检查其预测的增强能力，以重建功能丧失。虽然氨基硫醇的使用具有临床潜力，但需要更多的研究来完善特异性和治疗设计。氨基硫醇对靶蛋白的功效可根据其特定的细胞外和细胞内位置而显著变化。预计每个生理隔室中的氧化还原电位、pH和特定氨基硫醇丰度会影响半胱胺和类似药物的反应性和周转率。即将进行的研究将需要使用合适的细胞和动物模型，其特征是Arg到Cys突变。由于Arg到Cys的变化通常包含约8%的错义突变，因此这种特定突变的修复可能为许多遗传疾病提供有希望的途径。
Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.
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影响因子：
3.9
作者：
Balmer, Cecile;Pandey, Amit V.;Haeberle, Johannes
通讯作者：
Haeberle, Johannes
影响因子：
3.8
作者：
Besouw, Martine;Blom, Henk;Levtchenko, Elena
通讯作者：
Levtchenko, Elena
影响因子：
3.2
作者：
CAHILL, MC;GALLAGHER, GT;SZABO, S
通讯作者：
SZABO, S
影响因子：
4.1
作者：
GAHL, WA;TIETZE, F;SCHULMAN, JD
通讯作者：
SCHULMAN, JD
影响因子：
3.6
作者：
GAHL, WA;INGELFINGER, J;TANGERMAN, A
通讯作者：
TANGERMAN, A