Metal ion availability and homeostasis as drivers of metabolic evolution and enzyme function

Metal ions are potent catalysts and have been available for cellular biochemistry at all stages of evolution. Growing evidence suggests that metal catalysis was critical for the origin of the very first metabolic reactions. With approximately 80% of modern metabolic pathways being dependent on metal ions, metallocatalysis and homeostasis continue to be essential for intracellular metabolic networks and physiology. However, the genetic network that controls metal ion homeostasis and the impact of metal availability on metabolism is poorly understood. Here, we review recent work on gene and protein evolution relevant for better understanding metal ion biology and its role in metabolism. We highlight the importance of analysing the origin and evolution of enzyme catalysis in the context of catalytically relevant metal ions, summarise unanswered questions essential for developing a comprehensive understanding of metal ion homeostasis and advocate for the consideration of metal ion properties and availability in the design and directed evolution of novel enzymes and pathways.