Nature Communications, Published online: 22 August 2026; doi:10.1038/s41467-026-76869-7 Reductive amination catalysed by imine reductases and reductive aminases is a powerful method for the asymmetric synthesis of chiral amines, yet the generality and practical limitations of these enzymes remain poorly understood. Here, the authors combine large-scale, iterative activity screening, sequence analysis and machine-learning-guided exploration to profile reductive amination performance across 175 enzymes and structurally diverse substrate panels.