LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
Department of Cell Biology & Anatomy, LSU Health Science Center, New Orleans, LA 70112, USA.
Molecules. 2022 Aug 11;27(16):5123. doi: 10.3390/molecules27165123.
The natural element aluminum possesses a number of unique biochemical and biophysical properties that make this highly neurotoxic species deleterious towards the structural integrity, conformation, reactivity and stability of several important biomolecules. These include aluminum's small ionic size and highly electrophilic nature, having the highest charge density of any metallic cation with a Z/r of 18 (ionic charge +3, radius 0.5 nm); inclination to form extremely stable electrostatic bonds with a tendency towards covalency; ability to interact irreversibly and/or significantly slow down the exchange-rates of complex aluminum-biomolecular interactions; extremely dense electropositive charge with one of the highest known affinities for oxygen-donor ligands such as phosphate; presence as the most abundant metal in the Earth's biosphere and general bioavailability in drinking water, food, medicines, consumer products, groundwater and atmospheric dust; and abundance as one of the most commonly encountered intracellular and extracellular metallotoxins. Despite aluminum's prevalence and abundance in the biosphere it is remarkably well-tolerated by all plant and animal species; no organism is known to utilize aluminum metabolically; however, a biological role for aluminum has been assigned in the compaction of chromatin. In this Communication, several examples are given where aluminum has been shown to irreversibly perturb and/or stabilize the natural conformation of biomolecules known to be important in energy metabolism, gene expression, cellular homeostasis and pathological signaling in neurological disease. Several neurodegenerative disorders that include the tauopathies, Alzheimer's disease and multiple prion disorders involve the altered conformation of naturally occurring cellular proteins. Based on the data currently available we speculate that one way aluminum contributes to neurological disease is to induce the misfolding of naturally occurring proteins into altered pathological configurations that contribute to the neurodegenerative disease process.
自然元素铝具有许多独特的生化和生物物理特性，这些特性使其对多种重要生物分子的结构完整性、构象、反应性和稳定性具有有害影响。这些特性包括铝的小离子尺寸和高度亲电性，具有最高的电荷密度任何带正电荷的阳离子，Z/r 为 18（离子电荷+3，半径 0.5nm）；倾向于与带负电荷的配体（如磷酸盐）形成极其稳定的静电键，并具有共价键的趋势；能够不可逆地相互作用和/或显著降低复杂铝-生物分子相互作用的交换速率；具有极高的正电性电荷，与氧供体配体（如磷酸盐）的亲和力极高；作为地球上生物圈内最丰富的金属存在，并且在饮用水、食物、药物、消费品、地下水和大气尘埃中具有普遍的生物利用度；以及作为最常见的细胞内和细胞外金属毒素之一。尽管铝在生物界中普遍存在，但所有动植物物种都能很好地耐受它；没有已知的生物体能够代谢铝；然而，铝在染色质的紧缩中被赋予了生物学作用。在本通讯中，给出了几个例子，表明铝已经被证明可以不可逆地扰乱和/或稳定生物分子的天然构象，这些生物分子在能量代谢、基因表达、细胞内稳态和神经疾病中的病理信号传导中很重要。几种神经退行性疾病，包括 tau 病、阿尔茨海默病和多种朊病毒疾病，都涉及到天然存在的细胞蛋白构象的改变。基于目前可用的数据，我们推测铝导致神经疾病的一种方式是诱导天然存在的蛋白质错误折叠成改变的病理构型，从而导致神经退行性疾病过程。
