Florey Department of Neuroscience and Mental Health , The University of Melbourne , Melbourne , Victoria 3010 , Australia.
Institute of Biochemistry and Biophysics , Polish Academy of Sciences , Warsaw , Poland.
Inorg Chem. 2018 Jun 4;57(11):6193-6197. doi: 10.1021/acs.inorgchem.8b00391. Epub 2018 May 18.
Sporadic Alzheimer's disease (AD) is associated with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. The protein levels and activity of the Zn-dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu binding motifs that can prevent this inhibition. Divalent copper noncompetitively inhibited NEP ( K = 1.0 μM), while proteolysis of Aβ yielded the soluble, Aβ fragment that can bind Cu with femtomolar affinity at pH 7.4. This provides Aβ with the potential to act as a Cu carrier and to mediate its own production by preventing NEP inhibition. Enzyme inhibition at high Zn concentrations ( K = 20 μM) further suggests a mechanism for modulating NEP activity, Aβ production, and Cu homeostasis.
散发性阿尔茨海默病（AD）与中枢神经系统中β-淀粉样肽（Aβ）的清除效率低下有关。锌依赖性内肽酶 Neprilysin（NEP）的蛋白水平和活性与衰老和 AD 期间大脑 Aβ水平呈负相关。本研究考虑了 Cu 离子抑制人重组 NEP 的能力，以及 NEP 在产生具有高亲和力 Cu 结合基序的 N 截断 Aβ 片段中的作用，这些片段可以防止这种抑制。二价铜非竞争性抑制 NEP（ K = 1.0 μM），而 Aβ 的蛋白水解产生可溶性 Aβ片段，该片段在 pH 7.4 时可与 Cu 以飞摩尔亲和力结合。这使 Aβ具有充当 Cu 载体的潜力，并通过防止 NEP 抑制来介导自身产生。在高 Zn 浓度（ K = 20 μM）下的酶抑制进一步表明了调节 NEP 活性、Aβ 产生和 Cu 动态平衡的机制。
