Systems-Wide Prediction of Enzyme Promiscuity Reveals a New Underground Alternative Route for Pyridoxal 5’-Phosphate Production in E. coli

摘要: Recent insights suggest that non-specific and/or promiscuous enzymes are common and active across life. Understanding the role of such is an important open question in biology. Here we develop a genome-wide method, PROPER, uses permissive PSI-BLAST approach to predict activities metabolic genes. Enzyme promiscuity typically studied experimentally using multicopy suppression, which over-expression 'replacer' gene rescues lethality caused by inactivation 'target' gene. We use PROPER suppression Escherichia coli, achieving highly significant overlap with published cases (hypergeometric p = 4.4e-13). then validate three novel predicted target-replacer pairs new experiments. next go beyond network-based approach, GEM-PROPER, integrates genome-scale modeling replacements via alternative pathways. GEM-PROPER predicts indirect replacer (thiG) for essential enzyme (pdxB) production pyridoxal 5'-phosphate (the form Vitamin B6), suppression. perform structural analysis thiG determine its potential site, inactivating pertaining residues showing loss activity. Thus, this study successful example where computational investigation leads identification replacement key enzyme, would have been extremely difficult identify directly.