Mammalian dopa decarboxylase: Structure, catalytic activity and inhibition
Mammalian dopa decarboxylase: Structure, catalytic activity and inhibition
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DOI：
10.1016/j.abb.2013.12.020
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发表时间：
2014-03-15
影响因子：
3.9
通讯作者：
Bertoldi, Mariarita
中科院分区：
文献类型：
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作者：
Bertoldi, Mariarita
哺乳动物多巴脱羧酶催化L-多巴和L-5-羟色氨酸分别转化为多巴胺和5-羟色胺。这两种物质都是生物活性神经递质，其水平应该得到微调。事实上，多巴胺浓度的改变是神经退行性疾病的原因，如帕金森病。该酶的化学性质基于其辅酶吡哆醛5 '-磷酸（PLP）的特征。辅因子是高度反应性的，并且除了脱羧之外还能够进行多种反应，例如氧化脱氨基、半转氨基和Pictet-Spengler环化。结构解析表明，该酶具有二聚体的安排，并提供了分子基础，以确定参与每个催化活性的残基。这一信息已结合动力学研究在稳态和前稳态条件下作为pH值的函数，以阐明残留物的重要催化作用。DDC研究中的巨大努力致力于设计除了那些已经用于治疗中的抑制剂之外的有效和特异性抑制剂，所述抑制剂不是高度特异性的，并且是由临床方法对帕金森病或芳香族氨基酸脱羧酶缺乏症施加的副作用的原因。(C)2014爱思唯尔公司All rights reserved.
Mammalian Dopa decarboxylase catalyzes the conversion of L-Dopa and L-5-hydroxytryptophan to dopamine and serotonin, respectively. Both of them are biologically active neurotransmitters whose levels should be finely tuned. In fact, an altered concentration of dopamine is the cause of neurodegenerative diseases, such as Parkinson's disease. The chemistry of the enzyme is based on the features of its coenzyme pyridoxal 5'-phosphate (PLP). The cofactor is highly reactive and able to perform multiple reactions, besides decarboxylation, such as oxidative deamination, half-transamination and Pictet-Spengler cyclization. The structure resolution shows that the enzyme has a dimeric arrangement and provides a molecular basis to identify the residues involved in each catalytic activity. This information has been combined with kinetic studies under steady-state and pre-steady-state conditions as a function of pH to shed light on residues important for catalysis. A great effort in DDC research is devoted to design efficient and specific inhibitors in addition to those already used in therapy that are not highly specific and are responsible for the side effects exerted by clinical approach to either Parkinson's disease or aromatic amino acid decarboxylase deficiency. (C) 2014 Elsevier Inc. All rights reserved.