摘要
芳香族氨基酸羟化酶(AAAH)酶家族包括苯丙氨酸羟化酶(PAH),酪氨酸羟化酶(TH)和色氨酸羟化酶(TPH1和TPH2)。芳香族氨基酸羟化酶这四个家庭成员需要铁、氧和辅因子(6R)- l-赤式-5,6,7,8-四氢生物蝶呤(BH4)羟化作为各自的底物。芳香族氨基酸羟化酶参与严重的疾病;而在色氨酸羟化酶基因多态性与神经精神疾病相关的变异,并在苯丙氨酸羟化酶基因突变是负责的常染色体隐性遗传疾病,分别是苯丙酮尿症(PKU)和酪氨酸羟化酶缺陷(THD)。大量的苯丙酮尿症和酪氨酸羟化酶缺陷造成突变引起不稳定、错误折叠的蛋白质。构象不稳定的程度与病人的表型的严重程度,相关的搜索稳定的化合物,可能会保护从损失的蛋白质和活性在体内的相关性。与辅酶BH4补充对苯丙氨酸羟化酶的综合反应,其中的一个主要机制为苯丙氨酸羟化酶活性BH4反应苯丙酮尿症患者似乎是一个药物分子伴侣作用所致。酪氨酸羟化酶的稳定作用BH4是不成立的。另一方面,一批具有苯丙酮尿症和酪氨酸羟化酶缺陷突变体的药物分子伴侣潜在的化合物已被发现。在体外,在细胞和动物模型上已经建立了这些化合物的稳定作用。一次最近的研究显示药物分子伴侣作用不同的机制和确定的化合物,保存了活性弱结合的催化铁型。预计不同药物分子伴侣协同组合可以为病人量身定做的治疗方案。
关键词: 突变蛋白的稳定性,错误校正,药物分子伴侣,苯丙酮尿症,酪氨酸羟化酶缺乏症。
图形摘要
Current Drug Targets
Title:Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms
Volume: 17 Issue: 13
Author(s): Magnus Hole, Ana Jorge-Finnigan, Jarl Underhaug, Knut Teigen, Aurora Martinez
Affiliation:
关键词: 突变蛋白的稳定性,错误校正,药物分子伴侣,苯丙酮尿症,酪氨酸羟化酶缺乏症。
摘要: The aromatic amino acid hydroxylase (AAAH) enzyme family includes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2). All four members of the AAAH family require iron, dioxygen and the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) to hydroxylate their respective substrates. The AAAHs are involved in severe diseases; whereas polymorphisms and variants in the TPH genes are associated to neuropsychiatric disorders, mutations in PAH and TH are responsible for the autosomal recessive disorders phenylketonuria (PKU) and TH deficiency (THD), respectively. A large number of PKU and THD-causing mutations give rise to unstable, misfolded proteins. The degree of conformational instability correlates well with the severity of the patient phenotypes, underlying the relevance of searching for stabilizing compounds that may protect from loss of protein and activity in vivo. Supplementation with the cofactor BH4 exerts a multifactorial response in PAH, where one of the main mechanisms for the induced increase in PAH activity in BH4- responsive PKU patients appears to be a pharmacological chaperone effect. For TH the stabilizing effect of BH4 is less established. On the other hand, a number of compounds with pharmacological chaperone potential for PKU and THD mutants have been discovered. The stabilizing effect of these compounds has been established in vitro, in cells and in animal models. A recent study with TH has revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. It is expected that synergistic combinations of different pharmacological chaperones could provide patient-tailored therapeutic options.
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Cite this article as:
Magnus Hole, Ana Jorge-Finnigan, Jarl Underhaug, Knut Teigen, Aurora Martinez , Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms, Current Drug Targets 2016; 17 (13) . https://dx.doi.org/10.2174/1389450117666160307143512
DOI https://dx.doi.org/10.2174/1389450117666160307143512 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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