Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria
Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria
复制标题
DOI：
10.1007/164_2017_72
复制
发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Kraus, Jan P.
中科院分区：
文献类型：
--
作者：
Majtan, Tomas;Pey, Angel L.;Kraus, Jan P.
经典同型半胱氨酸尿症（HCU）是最常见的硫氨基酸代谢功能丧失性先天性疾病。 HCU 是由同型半胱氨酸酶促降解缺陷引起的，同型半胱氨酸是蛋氨酸转化为半胱氨酸的有毒中间体，主要是由于胱硫醚β合酶 (CBS) 基因的错义突变所致。与许多其他遗传性疾病一样，致病性突变并不针对关键的催化残基，而是引入结构扰动，导致突变体 CBS 错误折叠的趋势增强，或者形成非功能性聚集体，或者经历蛋白酶体依赖性降解。纠正 CBS 错误折叠将代表 HCU 的另一种治疗方法。在这篇综述中，我们总结了 CBS 的复杂性质、其多结构域结构、CBS 功能所需的三种辅助因子 [血红素、吡哆醛-5 0 -磷酸 (PLP) 和 S-腺苷甲硫氨酸 (SAM)] 之间的相互作用，以及由于 CBS 晶体学的进步而最近才被了解的复杂变构调节机制。虽然大约一半的患者对 PLP 前体吡哆醇治疗有反应，但许多研究表明小化学物质（例如化学和药理学伴侣或蛋白酶体抑制剂）的有用性，可以挽救 HCU 细胞和动物模型中的突变 CBS 活性。非特异性化学伴侣和蛋白酶体抑制剂有助于突变型 CBS 折叠过程和/或防止其快速降解，从而导致酶和 CBS 活性的稳态水平增加。最近对该领域的兴趣和可用的结构信息将有望通过使用新型配体的高通量筛选和计算模型来产生 CBS 特异性化合物，从而改善 CBS 突变体的折叠、稳定性和活性。
Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid 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 nonfunctional aggregates or to undergo proteasome-dependent degradation. Correction of CBS misfolding would represent an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multi-domain architecture, the interplay between the three cofactors required for CBS function [ heme, pyridoxal-5 0 -phosphate (PLP), and S-adenosylmethionine (SAM)], as well as the intricate allosteric regulatory mechanism only recently understood, thanks to advances in CBS crystallography. While roughly half of the patients respond 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 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 mutants.