Journal Article

Biocompatible aggregation-induced emission active polyphosphate-manganese nanosheets with glutamine synthetase-like activity in excitotoxic nerve cells

Chen, Yuncong, Yan, Li, Zhao, Xinyang, Wang, Xiuxiu, Huang, Yong, Zhao, Jing, Yu, Kuang, Wei, Wei, Wang, Jing, Hsu, Yi, Tao, Yucheng

2024

Overview

Glutamine synthetase (GS) is vital in maintaining ammonia and glutamate (Glu) homeostasis in living organisms. However, the natural enzyme relies on adenosine triphosphate (ATP) to activate Glu, resulting in impaired GS function during ATP-deficient neurotoxic events. To date, no reports demonstrate using artificial nanostructures to mimic GS function. In this study, we synthesize aggregation-induced emission active polyP-Mn nanosheets (STPE-PMNSs) based on end-labeled polyphosphate (polyP), exhibiting remarkable GS-like activity independent of ATP presence. Further investigation reveals polyP in STPE-PMNSs serves as phosphate source to activate Glu at low ATP levels. This self-feeding mechanism offers a significant advantage in regulating Glu homeostasis at reduced ATP levels in nerve cells during excitotoxic conditions. STPE-PMNSs can effectively promote the conversion of Glu to glutamine (Gln) in excitatory neurotoxic human neuroblastoma cells (SH-SY5Y) and alleviate Glu-induced neurotoxicity. Additionally, the fluorescence signal of nanosheets enables precise monitoring of the subcellular distribution of STPE-PMNSs. More importantly, the intracellular fluorescence signal is enhanced in a conversion-responsive manner, allowing real-time tracking of reaction progression. This study presents a self-sustaining strategy to address GS functional impairment caused by ATP deficiency in nerve cells during neurotoxic events. Furthermore, it offers a fresh perspective on the potential biological applications of polyP-based nanostructures. Glutamine synthetase (GS) relies on Adenosine triphosphate (ATP) to activate glutamate (Glu) and are vital for maintaining ammonia and Glu homeostasis, but GS function is impaired during ATP-deficient neurotoxic events. Here the authors report polyphosphate-manganese nanosheets having GS-like activity independent of ATP to promote the conversion of Glu to glutamine in excitatory neurotoxic cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 14 / 14/5 / 631/92/603 / 639/301/54/2295 / 639/638/45/957 / Adenosine triphosphate / Adenosine Triphosphate - metabolism / Ammonia / ATP / Biocompatibility / Biocompatible Materials - chemistry / Cell Line, Tumor / Emission / Emissions / Excitotoxicity / Fluorescence / Glutamate-ammonia ligase / Glutamate-Ammonia Ligase - metabolism / Glutamic Acid - metabolism / Glutamic Acid - toxicity / Glutamine / Glutamine - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Manganese / Manganese - chemistry / Manganese - metabolism / multidisciplinary / Nanosheets / Nanostructure / Nanostructures - chemistry / Nerves / Neuroblasts / Neurons - drug effects / Neurons - metabolism / Neurotoxicity / Polyphosphates - chemistry / Polyphosphates - metabolism / Polyphosphates - pharmacology / Polyps / Science / Science (multidisciplinary)