Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway.
Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway.
Biochimie. 2021 Apr;183:126-132. doi: 10.1016/j.biochi.2020.12.002. Epub 2020 Dec 10.
Tyrosine hydroxylase (TH) catalyses the (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)-dependent conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-Dopa), which is the rate-limiting step in the synthesis of dopamine and other catecholamine neurotransmitters and hormones. Dysfunctional mutant TH causes tyrosine hydroxylase deficiency (THD), characterized by symptoms ranging from mild l-Dopa responsive dystonia to severe neuropathy. THD-associated mutations often present misfolding and a propensity to aggregate, characteristics that can also be manifested by dysregulated wild-type TH. TH - and subsequently dopamine - is also reduced in Parkinson's disease (PD) due to the selective death of dopaminergic neurons. Thus, TH is a target for stabilizing small molecular weight compounds that can function as pharmacological chaperones, restoring enzyme folding and function. In this work we carried out a screening of a compound library with 1280 approved drugs and we identified levalbuterol, a beta2-adrenergic agonist that is broadly used in asthma treatment, as an interesting validated binder of human TH. Levalbuterol stabilized TH with reduced affinity compared to dopamine, the end-product and regulatory feedback inhibitor of TH, but without compromising enzymatic activity. Moreover, levalbuterol also delays the formation of TH aggregates and makes the enzyme less sensitive to dopamine, effects that could contribute to ameliorate disorders related to TH, such as THD and PD.
酪氨酸羟化酶（TH）催化（6R）-L-erythro-5,6,7,8-四氢生物蝶呤（BH4）依赖性将 L-酪氨酸转化为 L-3,4-二羟基苯丙氨酸（L-Dopa），这是多巴胺和其他儿茶酚胺神经递质和激素合成的限速步骤。功能失调的突变 TH 导致酪氨酸羟化酶缺乏症（THD），其特征是从轻度 L-Dopa 反应性肌张力障碍到严重神经病变的症状范围。与 THD 相关的突变通常表现出错误折叠和聚集倾向，这种特征也可以由失调的野生型 TH 表现出来。由于多巴胺能神经元的选择性死亡，TH 和随后的多巴胺在帕金森病（PD）中也减少。因此，TH 是稳定能够作为药理学伴侣发挥作用的小分子化合物的靶标，恢复酶的折叠和功能。在这项工作中，我们对包含 1280 种已批准药物的化合物库进行了筛选，并确定了利布特罗，一种广泛用于哮喘治疗的β2-肾上腺素能激动剂，是人类 TH 的一种有趣的有效结合物。与多巴胺（TH 的终产物和调节反馈抑制剂）相比，利布特罗稳定了 TH，但降低了亲和力，而不影响酶活性。此外，利布特罗还延迟了 TH 聚集体的形成，并使酶对多巴胺的敏感性降低，这些作用可能有助于改善与 TH 相关的疾病，如 THD 和 PD。
