Deep learning based kcat prediction enables improved enzyme constrained model reconstruction

Abstract

Enzyme turnover numbers (kcat values) are key parameters to understand cell metabolism, proteome allocation and physiological diversity, but experimentally measured kcat data are sparse and noisy. Here we provide a deep learning approach to predict kcat values for metabolic enzymes in a high-throughput manner with the input of substrate structures and protein sequences. Our approach can capture kcat changes for mutated enzymes and identify amino acid residues with great impact on kcat values. Furthermore, we applied the approach to predict genome scale kcat values for over 300 yeast species, demonstrating that the predicted kcat values are consistent with current evolutional understanding. Additionally, we designed an automatic pipeline using the predicted kcat values to parameterize enzyme-constrained genome scale metabolic models (ecGEMs) facilitated by a Bayesian approach, which outperformed the default ecGEMs in predicting phenotypes and proteomes and enabled to explain phenotype differences among yeast species. The deep learning kcat prediction approach and automatic ecGEM construction pipeline would thus be a valuable tool to uncover the global trend of enzyme kinetics and physiological diversity, and to further elucidate cell metabolism on a large scale.