Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383, Wroclaw, Poland.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106, Warsaw, Poland.
Dalton Trans. 2022 Sep 26;51(37):14267-14276. doi: 10.1039/d2dt02033e.
Preeclampsia is a blood pressure disorder associated with significant proteinuria. Hypertensive women have increased levels of neurokinin B (NKB) and Cu(II) ions in blood plasma during pregnancy. NKB bears the ATCUN/NTS N-terminal motif empowering strong Cu(II) binding in a characteristic four-nitrogen (4N) square-planar motif, but an alternative Cu(II)NKB geometry was proposed earlier. We studied the coordination of DMHD-NH, representing the NKB ATCUN/NTS motif, to Cu(II) by potentiometry, electronic absorption and circular dichroism spectroscopy in water and SDS micellar solutions. NKB was studied in SDS micelles. The experiments were aided by density functional theory (DFT) calculations. We found that under all investigated conditions NKB formed solely 1 : 1 complexes. In the absence of SDS, the 4N complex at physiological pH 7.4 has a very low dissociation constant of 3.5 fM, but the interaction with SDS weakened the binding nearly thousand-fold. This interaction may serve as a molecular switch for specific Cu(II) delivery to membrane receptors by NKB. Furthermore, the calculations based on clinical data indicate a potential toxic role of Cu(II)NKB in preeclampsia.
子痫前期是一种与显著蛋白尿相关的血压紊乱。妊娠期间，高血压女性的血浆中神经激肽 B (NKB) 和 Cu(II) 离子水平升高。NKB 具有 ATCUN/NTS N 端基序，能够在特征性的四氮 (4N) 平面四方基序中强力结合 Cu(II)，但之前提出了一种替代的 Cu(II)NKB 几何形状。我们通过电位法、电子吸收和圆二色性光谱法在水和 SDS 胶束溶液中研究了代表 NKB ATCUN/NTS 基序的 DMHD-NH 与 Cu(II) 的配位。在 SDS 胶束中研究了 NKB。实验得到了密度泛函理论 (DFT) 计算的帮助。我们发现，在所有研究的条件下，NKB 仅形成 1：1 配合物。在不存在 SDS 的情况下，生理 pH 值 7.4 下的 4N 配合物具有非常低的离解常数 3.5 fM，但与 SDS 的相互作用使结合力减弱近千倍。这种相互作用可能作为 NKB 将特定的 Cu(II) 递送至膜受体的分子开关。此外，基于临床数据的计算表明，Cu(II)NKB 在子痫前期中可能具有潜在的毒性作用。
