摘要
经典的高胱氨酸尿症(HCU)是最常见的与生俱来的含硫氨基酸代谢功能损失。它由在同型半胱氨酸酶降解不足引起的,一种有毒的蛋氨酸转化为半胱氨酸中间体,主要由于胱硫醚β-合成(CBS)基因错义突变。与许多其他遗传性疾病相比,致病突变目标关键不是催化残基,而是引入结构扰动导致增强的趋势突变胱硫醚β-合成错误折叠,形成无功能的聚集体或接受蛋白酶依赖的降解。因此,错误校正的胱硫醚β-合成代表高胱氨酸尿症的替代治疗方法。在这篇综述中,我们总结了胱硫醚β-合成的复杂性,其多畴结构,胱硫醚β-合成功能要求的3个辅因子之间的相互作用(血红素,磷酸吡哆醛(PLP)和S-腺苷甲硫氨酸)以及近段才解释说由于在胱硫醚β-合成的晶体学研究进展复杂的变构调节机制。在大约一半的患者对磷酸吡哆醛前驱吡哆醇治疗响应,许多研究表明小分子化合物的有用性,如化学和药物分子伴侣或蛋白酶体抑制剂,在高胱氨酸尿症的细胞和动物模型修复突变胱硫醚β-合成活性。非特定的化学分子伴侣和蛋白酶体抑制剂协助突变胱硫醚β-合成折叠过程和/或防止其快速降解,从而提高稳态水平的活性酶和胱硫醚β-合成。最近在该领域的关注度增加和可用的结构信息,将采用通过提高折叠的新型配体的高通量筛选和计算模型的特定化合物的胱硫醚β-合成,使胱硫醚β-合成具有稳定性和活性。
关键词: 经典的高胱氨酸尿症,胱硫醚合成酶,高通量筛选,同型半胱氨酸,药物分子伴侣蛋白的错误折叠,血红素,吡哆醛磷酸腺苷甲硫氨酸
图形摘要
Current Drug Targets
Title:Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions
Volume: 17 Issue: 13
Author(s): Tomas Majtan, Angel L. Pey, June Ereño-Orbea, Luis Alfonso Martínez-Cruz, Jan P. Kraus
Affiliation:
关键词: 经典的高胱氨酸尿症,胱硫醚合成酶,高通量筛选,同型半胱氨酸,药物分子伴侣蛋白的错误折叠,血红素,吡哆醛磷酸腺苷甲硫氨酸
摘要: Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acids metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine betasynthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form non-functional aggregates or to undergo proteasome-dependent degradation. Thus correction of CBS misfolding represents an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multidomain architecture, the interplay between the three cofactors required for CBS function (heme, pyridoxal-5’-phosphate (PLP) and S-adenosyl-L-methionine) as well as the intricate allosteric regulatory mechanism only recently explained thanks to advances in CBS crystallography. While roughly half of the patients responds to treatment with a PLP precursor pyridoxine, many studies suggested usefulness of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors, rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation, thus resulting in increased steady state levels of the enzyme and CBS activity. Recent increased interest in the field and available structural information will hopefully yield CBS-specific compounds by using high-throughput screening and computational modeling of novel ligands improving folding, stability and activity of CBS.
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Cite this article as:
Tomas Majtan, Angel L. Pey, June Ereño-Orbea, Luis Alfonso Martínez-Cruz, Jan P. Kraus , Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions, Current Drug Targets 2016; 17 (13) . https://dx.doi.org/10.2174/1389450117666160302094910
DOI https://dx.doi.org/10.2174/1389450117666160302094910 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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