Dhanavade Maruti J, Parulekar Rishikesh S, Kamble Subodh A, Sonawane Kailas D
Department of Microbiology, Shivaji University, Kolhapur 416004, Maharashtra (M.S.), India.
Structural Bioinformatics Unit, Department of Biochemistry, Shivaji University, Kolhapur 416004, Maharashtra (M.S.), India.
Mol Biosyst. 2016 Jan;12(1):162-8. doi: 10.1039/c5mb00718f.
The pathological hallmark of Alzheimer's disease is the accumulation of Aβ peptides in human brains. These Aβ peptides can be degraded by several enzymes such as hACE, hECE, hIDE and cathepsin B. Out of which cathepsin B also belongs to the papain super family and has been found in human brains, it has a role in Aβ peptide degradation through limited proteolysis. The Aβ concentrations are maintained properly by its production and clearance via receptor-mediated cellular uptake and direct enzymatic degradation. However, the reduced production of Aβ degrading enzymes as well as their Aβ degrading activity in human brains initiate the process of accumulation of Aβ peptides. So it becomes essential to investigate the molecular interactions involved in the process of Aβ degradation in detail at the atomic level. Hence, homology modeling, molecular docking and molecular dynamics simulation techniques have been used to explore the possible role of cathepsin B from Hordeum vulgare in the degradation of amyloid beta (Aβ) peptides. The homology model of cathepsin B from Hordeum vulgare shows good similarity with human cathepsin B. Molecular docking and MD simulation results revealed that the active site residues Cys32, HIS112, HIS113 are involved in the catalytic activity of cathepsin B. The sulfhydryl group of the Cys32 residue of cathepsin B from Hordeum vulgare cleaves the Aβ peptide from the carboxylic end of Glu11. Hence, this structural study might be helpful in designing alternative strategies for the treatment of AD.
阿尔茨海默病的病理标志是人类大脑中β淀粉样蛋白（Aβ）肽的积累。这些Aβ肽可被多种酶降解，如人血管紧张素转换酶（hACE）、人内皮素转换酶（hECE）、人胰岛素降解酶（hIDE）和组织蛋白酶B。其中组织蛋白酶B也属于木瓜蛋白酶超家族，且已在人类大脑中发现，它通过有限的蛋白水解作用参与Aβ肽的降解。Aβ的浓度通过其生成以及经由受体介导的细胞摄取和直接酶促降解的清除作用得以适当维持。然而，人类大脑中Aβ降解酶的生成减少及其Aβ降解活性引发了Aβ肽的积累过程。因此，在原子水平详细研究Aβ降解过程中涉及的分子相互作用变得至关重要。因此，已使用同源建模、分子对接和分子动力学模拟技术来探索大麦中的组织蛋白酶B在淀粉样β（Aβ）肽降解中的可能作用。大麦组织蛋白酶B的同源模型与人组织蛋白酶B具有良好的相似性。分子对接和分子动力学模拟结果表明，活性位点残基半胱氨酸32（Cys32）、组氨酸112（HIS112）、组氨酸113（HIS113）参与了组织蛋白酶B的催化活性。大麦组织蛋白酶B的Cys32残基的巯基从谷氨酸11（Glu11）的羧基末端切割Aβ肽。因此，这项结构研究可能有助于设计治疗阿尔茨海默病的替代策略。
