Cell Biology and Neurobiology Branch, National Institutes of Child Health and Human, Development, National Institutes of Health, Bethesda, Maryland, USA.
Cell Biology and Neurobiology Branch, National Institutes of Child Health and Human, Development, National Institutes of Health, Bethesda, Maryland, USA.
J Biol Chem. 2024 Aug;300(8):107589. doi: 10.1016/j.jbc.2024.107589. Epub 2024 Jul 19.
Transition metal ions are critically important across all kingdoms of life. The chemical properties of iron, copper, zinc, manganese, cobalt, and nickel make them very attractive for use as cofactors in metalloenzymes and/or metalloproteins. Their versatile chemistry in aqueous solution enables them to function both as electron donors and acceptors, and thus participate in both reduction and oxidation reactions respectively. Transition metal ions can also function as nonredox multidentate coordination sites that play essential roles in macromolecular structure and function. Malfunction in transition metal transport and homeostasis has been linked to a wide number of human diseases including cancer, diabetes, and neurodegenerative disorders. Transition metal transporters are central players in the physiology of transition metals whereby they move transition metals in and out of cellular compartments. In this review, we provide a comprehensive overview of in vitro reconstitution of the activity of integral membrane transition metal transporters and discuss strategies that have been successfully implemented to overcome the challenges. We also discuss recent advances in our understanding of transition metal transport mechanisms and the techniques that are currently used to decipher the molecular basis of transport activities of these proteins. Deep mechanistic insights into transition metal transport systems will be essential to understand their malfunction in human diseases and target them for potential therapeutic strategies.
过渡金属离子在所有生命领域都至关重要。铁、铜、锌、锰、钴和镍的化学性质使它们非常适合作为金属酶和/或金属蛋白的辅因子。它们在水溶液中的多功能化学性质使它们既能作为电子供体又能作为电子受体，从而分别参与还原和氧化反应。过渡金属离子还可以作为非氧化多齿配位基，在大分子结构和功能中发挥重要作用。过渡金属转运和动态平衡的功能障碍与许多人类疾病有关，包括癌症、糖尿病和神经退行性疾病。过渡金属转运蛋白是过渡金属生理学的核心参与者，它们将过渡金属进出细胞区室。在这篇综述中，我们全面概述了整合膜过渡金属转运蛋白活性的体外重建，并讨论了成功实施的克服挑战的策略。我们还讨论了我们对过渡金属转运机制的理解的最新进展，以及目前用于破译这些蛋白质转运活性的分子基础的技术。深入了解过渡金属转运系统对于理解它们在人类疾病中的功能障碍以及针对这些疾病的潜在治疗策略至关重要。
