Finding branched pathways in metabolic network via atom group tracking

Finding non-standard or new metabolic pathways has important applications in metabolic engineering, synthetic biology and the analysis and reconstruction of metabolic networks. Branched metabolic pathways dominate in metabolic networks and depict a more comprehensive picture of metabolism compared to linear pathways. Although progress has been developed to find branched metabolic pathways, few efforts have been made in identifying branched metabolic pathways via atom group tracking. In this paper, we present a pathfinding method called BPFinder for finding branched metabolic pathways by atom group tracking, which aims to guide the synthetic design of metabolic pathways. BPFinder enumerates linear metabolic pathways by tracking the movements of atom groups in metabolic network and merges the linear atom group conserving pathways into branched pathways. Two merging rules based on the structure of conserved atom groups are proposed to accurately merge the branched compounds of linear pathways to identify branched pathways. Furthermore, the integrated information of compound similarity, thermodynamic feasibility and conserved atom groups is also used to rank the pathfinding results for feasible branched pathways. Experimental results show that BPFinder is more capable of recovering known branched metabolic pathways as compared to other existing methods, and is able to return biologically relevant branched pathways and discover alternative branched pathways of biochemical interest. The online server of BPFinder is available at http://114.215.129.245:8080/atomic/. The program, source code and data can be downloaded from https://github.com/hyr0771/BPFinder.Author summary: Computational search of branched metabolic pathways is a fundamental problem in metabolic engineering and metabolic network analysis, which provides a systematic way of understanding the metabolism and discovering alternative pathways for synthesis of useful biomolecules. We propose BPFinder, a novel computational approach to identify branched metabolic pathways via atom group tracking. Different from other pathfinding methods using atom tracking, BPFinder tracks the movement of atom groups in metabolic network to find linear atom group conserving pathways, and merge the found linear pathways by the selected branched compounds to generate branched pathways. Based on the structure of conserved atom groups in branched compounds, we design two merging rules for branched compounds: overlapping rule and non-overlapping rule. The user can flexibly adopt these rules to accurately find the branched pathways that contain overlapping/non-overlapping conserved atom groups. BPFinder also enables the user to combine the information of compound similarity, Gibbs free energy of reactions, and conserved atom groups to sort resulting pathways. Compared with other existing methods, BPFinder can more accurately recover the known branched pathways. The alternative branched pathways returned by BPFinder reveal that the user can flexibly utilize our proposed merging rules to discover biochemically meaningful pathways of interest.