Laboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Ljubljana 1000, Slovenia.
Networking Infrastructure Centre, Jožef Stefan Institute, Ljubljana 1000, Slovenia.
J Phys Chem B. 2024 Sep 5;128(35):8355-8361. doi: 10.1021/acs.jpcb.4c03002. Epub 2024 Aug 24.
L-DOPA, or levodopa, plays an important role in the treatment of Parkinson's disease, a debilitating neurological disorder. It acts as a precursor to dopamine, a neurotransmitter crucial for the regulation of motor functions. Administered orally, L-DOPA easily crosses the blood-brain barrier and converts into dopamine in the brain, relieving symptoms such as tremors and rigidity. However, its prolonged use can lead to complications. A significant concern with L-DOPA is its conversion to dopaquinone, a quinone metabolite that enters the redox cycle and continuously produces hydrogen peroxide. In addition, L-DOPA, which resembles tyrosine with an additional hydroxyl group, can randomly incorporate into the proteins of dopaminergic neurons and thus become an additional source of oxidative stress in Parkinson's patients. In this study, we scrutinized the rate-limiting step of L-DOPA autoxidation in aqueous solution. The reaction we studied is an intramolecular Michael addition concerted with a proton transfer from the amino group. Using the Empirical Valence Bond (EVB) method, we computed the free energy profiles of the reaction in water. The calculated barrier of 30.93 ± 1.12 kcal/mol is in reasonable agreement with the experimental barrier of 27.55 kcal/mol. This agreement confirms the validity of the studied mechanism and demonstrates the applicability of our simulation methodology for studying the autoxidation kinetics of L-DOPA within proteins.
L-多巴，即左旋多巴，在帕金森病的治疗中起着重要作用，帕金森病是一种使人虚弱的神经退行性疾病。它是多巴胺的前体，而多巴胺是调节运动功能的关键神经递质。L-多巴经口服给药时，很容易穿过血脑屏障，并在大脑中转化为多巴胺，从而缓解震颤和僵硬等症状。然而，其长期使用可能会导致并发症。L-多巴的一个重要问题是它会转化为多巴醌，一种醌代谢物，进入氧化还原循环，并不断产生过氧化氢。此外，L-多巴与额外的羟基相似，可随机掺入多巴胺能神经元的蛋白质中，从而成为帕金森病患者氧化应激的另一个来源。在这项研究中，我们仔细研究了水溶液中 L-多巴自动氧化的限速步骤。我们研究的反应是一个分子内迈克尔加成，伴随着氨基的质子转移。使用经验价键 (EVB) 方法，我们计算了水中反应的自由能曲线。计算得到的 30.93±1.12 kcal/mol 的能垒与实验得到的 27.55 kcal/mol 的能垒相当吻合。这种一致性证实了所研究的机制的有效性，并表明我们的模拟方法可用于研究蛋白质内 L-多巴自动氧化动力学。
