Lehrer Steven, Rheinstein Peter H
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1236, New York, NY 10029, USA.
Severn Health Solutions, Severna Park, MD, USA.
J Proteins Proteom. 2022 Jun;13(2):109-115. doi: 10.1007/s42485-022-00088-z. Epub 2022 May 21.
Parkinson's disease (PD) results from degeneration of dopamine and norepinephrine neurons due to α-synuclein aggregates that likely have their origin in the gut. Tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine. A second enzyme, DOPA decarboxylase (DDC), catalyzes the conversion of L-DOPA to dopamine. A third enzyme, dopamine ß-hydroxylase (DBH), catalyzes the conversion of dopamine to norepinephrine. To analyze possible interactions of α-synuclein with TH, DDC and DBH, we performed in silico protein-protein docking.
Protein data bank (pdb) entries were searched on the RCSB Protein Data Bank. We identified four structures that allowed us to examine the relationship of α-synuclein with TH, DDC, and DBH: (1) Human micelle-bound alpha-synuclein, (2) solution structure of the regulatory domain of tyrosine hydroxylase (), (3) crystal structure of human aromatic L-amino acid decarboxylase (DOPA decarboxylase) in the apo form and (4) crystal structure of human dopamine ß-hydroxylase at 2.9 angstrom resolution. We used the ClusPro server (https://cluspro.org) for protein-protein docking. The protein structures were visualized with PyMOL v 2.3.4.
α-synuclein partially enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. α-synuclein may dock too far away from DOPA decarboxylase to affect its function directly.
Our in silico finding of α-synuclein partly enfolding tyrosine hydroxylase and dopamine ß-hydroxylase suggests that α-synuclein docking inhibition could increase dopamine and norepinephrine biosynthesis, ameliorating PD symptoms. Small molecules that bind to α-synuclein have already been identified. Further studies may lead to new small molecule drugs that block α-synuclein enfolding of tyrosine hydroxylase and dopamine ß-hydroxylase.
帕金森病（PD）是由于α-突触核蛋白聚集体导致多巴胺能和去甲肾上腺素能神经元变性所致，这些聚集体可能起源于肠道。酪氨酸羟化酶（TH）催化L-多巴的形成，这是多巴胺生物合成中的限速步骤。第二种酶，多巴脱羧酶（DDC），催化L-多巴转化为多巴胺。第三种酶，多巴胺β-羟化酶（DBH），催化多巴胺转化为去甲肾上腺素。为了分析α-突触核蛋白与TH、DDC和DBH之间可能的相互作用，我们进行了计算机辅助蛋白质-蛋白质对接。
在RCSB蛋白质数据库中搜索蛋白质数据库（pdb）条目。我们确定了四个结构，可用于研究α-突触核蛋白与TH、DDC和DBH的关系：（1）人胶束结合的α-突触核蛋白，（2）酪氨酸羟化酶调节域的溶液结构，（3）脱辅基形式的人芳香族L-氨基酸脱羧酶（多巴脱羧酶）的晶体结构，以及（4）分辨率为2.9埃的人多巴胺β-羟化酶的晶体结构。我们使用ClusPro服务器（https://cluspro.org）进行蛋白质-蛋白质对接。使用PyMOL v 2.3.4可视化蛋白质结构。
α-突触核蛋白部分包裹酪氨酸羟化酶和多巴胺β-羟化酶，可能会减少多巴胺和去甲肾上腺素的合成。α-突触核蛋白与多巴脱羧酶的对接距离可能太远，无法直接影响其功能。
我们在计算机模拟中发现α-突触核蛋白部分包裹酪氨酸羟化酶和多巴胺β-羟化酶，这表明抑制α-突触核蛋白对接可能会增加多巴胺和去甲肾上腺素的生物合成，改善帕金森病症状。已经鉴定出与α-突触核蛋白结合的小分子。进一步的研究可能会导致新的小分子药物，阻止α-突触核蛋白对酪氨酸羟化酶和多巴胺β-羟化酶的包裹。
