How to fix a broken protein: restoring function to mutant human cystathionine β-synthase.
How to fix a broken protein: restoring function to mutant human cystathionine β-synthase.
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如何修复受损的蛋白质：恢复突变型人类胱硫醚β-合酶的功能。
DOI：
10.1007/s00439-021-02386-w
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发表时间：
2022-07
期刊：
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
先天性代谢错误(IEM)包括一大类隐性遗传病，涉及细胞代谢紊乱，这些疾病往往是由错义突变引起的，即多肽链中一个错误的氨基酸被取代。胱硫醚-β-合酶(CBS)缺乏是IEM的一个例子，它导致血液中总同型半胱氨酸水平大幅升高，导致几个组织的表型。目前的治疗策略包括饮食限制和维生素治疗，但这些只有部分有效，并不是对所有患者都有效。在CBS缺陷患者中，超过85%的突变是错义突变，其中突变蛋白无法折叠成活性构象。CBS获得活性构象的能力受到多种细胞内蛋白质网络的影响，包括伴侣系统和泛素/蛋白酶体系统，统称为蛋白质平衡网络。蛋白平衡调节剂是扰乱这些网络的各个方面的药物。在这篇文章中，我们将回顾调节细胞内蛋白质折叠环境可以作为治疗CBS缺乏症的一种潜在治疗策略的证据，并讨论这种策略的利弊。
Inborn errors of metabolism (IEM) comprise a large class of recessive genetic diseases involving disorders of cellular metabolism that tend to be caused by missense mutations in which a single incorrect amino acid is substituted in the polypeptide chain. Cystathionine beta-synthase (CBS) deficiency is an example of an IEM that causes large elevations of blood total homocysteine levels resulting in phenotypes in several tissues. Current treatment strategies involve dietary restriction and vitamin therapy, but these are only partially effective and do not work in all patients. Over 85% of the described mutations in CBS deficient patients are missense mutations in which the mutant protein fails to fold into an active conformation. The ability of CBS to achieve an active conformation is affected by a variety of intracellular protein networks including the chaperone system and the ubiquitin/proteasome system, collectively referred to as the proteostasis network. Proteostasis modulators are drugs that perturb various aspects of these networks. In this article, we will review the evidence that modulation of the intracellular protein-folding environment can be used as a potential therapeutic strategy to treat CBS deficiency and discuss the pros and cons of such a strategy.