Web Exclusives: Structural Biology
Metabolic Network Takes Shape
Like cartographers including mountain peaks or river channels to give dimension to a flat map, a research team has added a third dimension—protein structures—to its map of a metabolic network. The new picture could lead to insights about basic biology and evolution.
For more than 150 years, researchers interested in life's origins have studied metabolic networks, the collection of biochemical reactions that drive crucial cellular activities. To date, they've found metabolic similarities in a wide range of creatures, from bacteria to blue whales, suggesting that many biochemical reactions have been conserved from a very early ancestor.
In mapping metabolic networks, scientists have usually focused just on biochemical reactions and metabolic products. They have not included the structures of proteins that carry out most of the activities and can give a more complete understanding of metabolic networks and their parts.
That's because this structural information hasn't been available until recently. Large-scale structure determination projects like the NIH's Protein Structure Initiative (PSI) are churning out thousands of different three-dimensional protein shapes that researchers can use to computationally generate many thousands more. This now lets researchers like Adam Godzik, a computational biologist at the Burnham Institute for Medical Research, generate the structures of all the proteins in a metabolic network.
Considered the first achievement of its kind, Godzik and his colleagues have used a combination of protein structures determined experimentally and computationally to create a comprehensive view of the central metabolic network of the heat-loving bacterium Thermotoga maritima.
The researchers picked T. maritima in part because it has a relatively small, fully sequenced genome (making it easier to map its metabolic network) and it has the deepest lineages of the Eubacteria kingdom (making it a good place to learn more about evolution). Plus, the PSI Joint Center for Structural Genomics had already experimentally determined a relatively large number of the organism's protein structures.
The new model includes the structures of all 478 proteins in the metabolic network, along with 645 chemical reactions and 503 metabolic products. Building it, Godzik says, was truly a team effort that involved biochemists, enzymologists, structural biologists, systems biologists and computational modelers.
Godzik says the most significant finding of the new work is that the central metabolism of T. maritima is performed by a "surprisingly small" set of three-dimensional protein shapes that dictate a wide range of related and often essential functions. These shapes can help us understand why organisms have retained certain metabolic similarities and how they gain new metabolic capabilities.
"While we've reached an important milestone, this is only the beginning," says Godzik, who also directs the PSI Joint Center for Molecular Modeling.
Working with collaborators at The Scripps Research Institute and University of California, San Diego, Godzik plans to use the new map to explore other details about T. maritima's metabolism—perhaps even how we can harness its ability to generate hydrogen from organic waste to produce clean energy. He also wants to use the structural approach to map the metabolic networks of other organisms and develop similar models of human cells, which could aid disease diagnosis and treatment.
The new work is described in the September 18 issue of Science and was supported by NIH's National Institute of General Medical Sciences and the Department of Energy.