Therefore, in the local reaction dataset, these molecules were removed from the reaction entries for the purpose of reaction prediction and enzyme prediction. However, although these molecules are freely available in cell environments, for example NADPH is a coenzyme in anabolic reactions as a reducing agent and it is maintained at a stable concentration in a cell by pentose phosphate pathway for reduction of bio-active molecules, in industrial enzymatic processes, cofactors are difficult to recycle and recover, making cofactor-dependent biochemical transformations potentially economically unviable. Cofactors are frequently important to enzymatic reactions since certain reactions are cofactor-specific and the cofactor could affect the product yield. These aspects were not addressed in the present work. Future work will aim to integrate cofactor and metabolite data to provide a more detailed and accurate model of enzymatic activity, which could significantly enhance the applicability of our findings. A list of cofactors and free metabolites from KEGG database was manually curated by Blaβ et al. The full lists can be found in Section S1 of Electronic Supplementary Information (ESI).