Compartmentalization of the Edinburgh Human Metabolic Network.

Direct in vivo investigation of human metabolism is complicated by the distinct metabolic functions of various sub-cellular organelles. Diverse micro-environments in different organelles may lead to distinct functions of the same protein and the use of different enzymes for the same metabolic reaction. To better understand the complexity in the human metabolism, a compartmentalized human metabolic network with integrated sub-cellular location information is required. We extended the previously reconstructed Edinburgh Human Metabolic Network (EHMN) [Ma, et al. Molecular Systems Biology, 3:135, 2007] by integrating the sub-cellular location information for the reactions, adding transport reactions and refining the protein-reaction relationships based on the location information. Firstly, protein location information was obtained from Gene Ontology and complemented by a Swiss-Prot location keywords search. Then all the reactions in EHMN were assigned to a location based on the protein-reaction relationships to get a preliminary compartmentalized network. We investigated the localized sub-networks in each pathway to identify gaps and isolated reactions by connectivity analysis and refined the location information based on information from literature. As a result, location information for hundreds of reactions was revised and hundreds of incorrect protein-reaction relationships were corrected. Over 1400 transport reactions were added to link the location specific metabolic network. To validate the network, we have done pathway analysis to examine the capability of the network to synthesize or degrade certain key metabolites. Compared with a previously published human metabolic network (Human Recon 1), our network contains over 1000 more reactions assigned to clear cellular compartments. By combining protein location information, network connectivity analysis and manual literature search, we have reconstructed a more complete compartmentalized human metabolic network. The whole network is available at http://www.ehmn.bioinformatics.ed.ac.uk and free for academic use.