Wißbrock Amelie, Kühl Toni, Silbermann Katja, Becker Albert J, Ohlenschläger Oliver, Imhof Diana
Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn , Brühler Strasse 7, 53119 Bonn, Germany.
Institute of Neuropathology, University Hospital Bonn , Sigmund Freud Strasse 25, 53105 Bonn, Germany.
J Med Chem. 2017 Jan 12;60(1):373-385. doi: 10.1021/acs.jmedchem.6b01432. Epub 2016 Dec 15.
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.
不稳定血红素已被认为对几种严重疾病有影响。然而，在阿尔茨海默病（AD）的背景下，已有报道称游离血红素水平降低。因此，我们一直在寻找一种可用于测定血红素浓度的检测系统。从生化角度来看，Aβ-血红素复合物的过氧化物酶活性似乎对实现这一目标颇具吸引力。因此，即使在血红素浓度较低的情况下，能够增加读数的肽是有利的。对与血红素复合的Aβ衍生肽和非Aβ衍生肽的研究表明，过氧化物酶样活性显著取决于肽的序列和长度。一种源自人脂肪酰辅酶A还原酶1的与血红素复合的23聚体组氨酸基肽表现出比Aβ(40)-血红素显著更高的过氧化物酶活性。两种复合物的结构建模表明，通过组氨酸的血红素结合可以由原卟啉IX丙酸羧基功能附近的碱性残基的氢键相互作用来支持。此外，还研究了Aβ-血红素与作为Aβ潜在生理效应物的脂蛋白LDL之间的相互作用。
