Research On Structure, Function And Evolution Of Cellular Metabolic Networks

Cellular metabolism is essential for the maintenance of life. In metabolic process, through specific biochemical reactions, some materials are broken down to yield energy for vital processes while other substances, necessary for life, are synthesized. All metabolic reactions occurring within a living cell of an organism constitute the metabolic network of this organism. Although a large variety of metabolic reactions can be found in different organisms, metabolic networks are highly conserved across them. As the results of various genome projects, the genome sequences of many organisms are available and the organism specific metabolic networks can be faithfully reconstructed from genome information. Thus the prediction of function from the metabolic networks has become an essential step in the post-genomic era. The analysis of metabolic networks can help to understand and utilize cellular metabolic process in order to promote the development of ferment technology and medicine industry. On the other hand, the topology of metabolic networks reflects the dynamics of their formation and evolution, studying of which may help to understand the evolutionary history of life.In this thesis, the interplay between topology, function and evolution were studied by exploring the structural features of metabolic networks. The metabolic networks of 75 organisms including 8 eukaryote, 56 bacteria and 11 archaea were constructed based on existing metabolic databases. The common topological features of these networks were identified, and the functional and evolutionary significance of these structural properties were investigated.First, the global topological feature of metabolic networks was studied. A spread bow-tie model was proposed to give a clear visualization of the macroscopic bow-tie structure for metabolic networks. The revealed topological pattern helps to design more efficient algorithm specifically for metabolic networks. This coarse-grained graph also visualizes the vulnerable connections in the network, and thus could have important implication for disease studies and drug target identifications. Our further investigation to the bow-tie structure of metabolic networks suggests that the bow-tie knot (GSC) enriches bi-directed links and includes a densely connected main core. Remarkably, the three major pathways– glycolysis, tricarboxylic acid (TCA) and pentose phosphate pathway take up most of the reactions in the main cores. This feature suggests the functional significance of bow-tie structure in keeping the robustness of metabolic system.Then the research focused on the modular topological feature of metabolic networks. The problem was studied from two aspects as follows.First, the hierarchically modular feature of nested bow-ties in metabolic networks was studied. An algorithm was proposed to split the metabolic network into sub-networks based on the global bow-tie topology of metabolic networks. Network decomposition of three microbes (Escherichia coli, Aeropyrum pernix and Saccharomyces cerevisiae) shows that almost all of the sub-networks exhibit a highly modularized bow-tie topological pattern similar to that of the global metabolic networks. These small bow-ties are hierarchically nested into larger ones and collectively integrated into a large metabolic network, and important features of this modularity are not observed in the random shuffled network. Moreover, a large fraction of bow-tie modules overlap with functional modules. In addition, such a bow-tie pattern appears to be present in certain chemically isolated functional modules and spatially separated modules including carbohydrate metabolism, cytosol and mitochondrion respectively. This study shows that the highly modularized bow-tie pattern is present at different levels and scales, and in different chemical and spatial modules of metabolic networks, which is likely the result of the evolutionary process rather than a random accident. This result could be helpful for understanding the design principles and facilitate the modelling of metabolic networks.Second, the core-periphery modular feature of metabolic networks was explored. The Homo sapiens (H. sapiens) metabolic network was broken into sub-networks by simulation annealing. Network decomposition shows that the metabolic network is organized in a highly modular core-periphery way, in which the core modules are tightly linked together and perform basic metabolism functions, whereas the periphery modules only interact with few modules and accomplish relatively independent and specialized functions. Moreover, over half of the modules exhibit co-evolutionary feature and belong to specific evolutionary ages. Peripheral modules tend to evolve more cohesively and faster than core modules do. Such systems level analysis could demonstrate how the evolution of genes may be placed in a genome-scale network context, giving a novel perspective on molecular evolution.In conclusion, the study in this thesis reveals the correlation between topology, function, and evolution of metabolic networks, suggesting that the evolutionary history and functional requirements of metabolic systems have been imprinted in the architecture of metabolic networks. This study may shed light on a more global understanding of the topology, function and evolution for metabolic networks.