Synthesis and Evaluation of Amyloid β Derived and Amyloid β Independent Enhancers of the Peroxidase-like Activity of Heme

Labile heme has been suggested to have an impact in several severe diseases. In the context of Alzheimer’s disease (AD), however, decreased levels of free heme have been reported. Therefore, we were looking for an assay system that can be used for heme concentration determination. From a biochemical point of view the peroxidase activity of the Aβ-heme complex seemed quite attractive to pursue this goal. As a consequence, a peptide that is able to increase the readout even in the case of a low heme concentration is favorable. The examination of Aβ- and non-Aβ-derived peptides in complex with heme revealed that the peroxidase-like activity significantly depends on the peptide sequence and length. A 23mer His-based peptide derived from human fatty acyl-CoA reductase 1 in complex with heme exhibited a significantly higher peroxidase activity than Aβ(40)-heme. Structural modeling of both complexes demonstrated that heme binding via a histidine can be supported by hydrogen bond interactions of a basic residue near the propionate carboxyl function of protoporphyrin IX. Furthermore, the interplay of Aβ-heme and the lipoprotein LDL as a potential physiological effector of Aβ was examined.不稳定血红素（labile heme）被认为可影响多种重症疾病的病理进程。然而在阿尔茨海默病（AD）的研究背景下，已有报道显示游离血红素的水平有所降低。为此，我们亟需开发一种可用于血红素浓度定量检测的分析体系。从生物化学视角来看，β淀粉样蛋白-血红素（Aβ-heme）复合物的过氧化物酶活性（peroxidase activity）似乎是实现该检测目标的极具潜力的研究方向。因此，即便在血红素浓度较低的情况下，也能增强检测信号的多肽将是理想的候选分子。对与血红素结合的Aβ来源与非Aβ来源多肽的检测分析显示，其类过氧化物酶活性显著依赖于多肽的序列与长度。其中，源自人脂酰辅酶A还原酶1（fatty acyl-CoA reductase 1）的23个氨基酸残基的组氨酸基多肽，与血红素结合后所展现的过氧化物酶活性，显著高于Aβ(40)-血红素复合物。对两种复合物的结构建模结果表明，通过组氨酸残基结合的血红素，可借助原卟啉IX（protoporphyrin IX）丙酸羧基官能团附近的碱性残基所形成的氢键相互作用得到稳定。此外，本研究还探究了Aβ-血红素复合物与脂蛋白低密度脂蛋白（LDL）——作为Aβ潜在生理效应因子——之间的相互作用。