Building a Complete Metabolic Model

Investigators at Burnham Institute for Medical Research (Burnham), University of California, San Diego (UC San Diego), The Scripps Research Institute (TSRI), Genomics Institute of the Novartis Research Foundation (GNF) and other institutions have constructed a complete model, including three dimensional protein structures, of the central metabolic network of the bacterium Thermotoga maritima (T. maritima).

This is the first time scientists have developed such a comprehensive model of a metabolic network overlaid with an atomic resolution of network proteins. The analysis of the model, among others, highlights the important role of a small number of essential protein shapes, lending new insights into the evolution of protein networks and the functions within these networks. The study was published in the journal Science on September 18.

Combining biochemical studies, structural genomics and computer modeling, the researchers deciphered the shapes, functions and interactions of 478 proteins that make up T. maritima’s central metabolism. The team also found connections between these proteins and 503 unique metabolites in 562 intracellular and 83 extracellular metabolic reactions.

“We have built an actual three dimensional model of every protein in the central metabolic system,” said Adam Godzik, Ph.D., director of Burnham’s Bioinformatics and Systems Biology program. “We got the whole thing. This is analogous to sequencing an entire genome.”

With this data, scientists can simulate metabolism simultaneously on a biochemical and molecular level. This information has the promise to expand computer modeling to allow investigators to simulate the interactions between proteins and various compounds in an entire system. Furthermore, the procedure developed in this study could be applied to study many other organisms, including humans. It could potentially help identify both positive and adverse drug reactions before pre-clinical and clinical trials. The research may also have applications in energy research, as bacteria like T. maritima can be engineered to more efficiently produce hydrogen, a key source of clean energy.

“In addition to the systematic analysis of interacting components, the next challenge is addressing the levels or scales of biological organization, ranging from molecules to an individual and even to populations,” said co-author John C. Wooley, Ph.D., of UC San Diego’s Center for Research in Biological Systems and the California Institute for Telecommunications and Information Technology. “This work, by including both functional and architectural details, takes that first step and provides a novel, enriched view of the complexity of life.”

Researchers were surprised by the degree of structural conservation within the network. Of the 478 proteins, with 714 domains, there were only 182 distinct folds. This supports the hypothesis that nature uses existing shapes, slightly modified, to perform new tasks.

The team used genomic, metabolic, and structural reconstruction to determine the network down to the atomic level. They then classified metabolic reactions based on whether they were similar, connected or unrelated and found that enzymes that catalyze similar reactions have a higher probability of having similar folds. In addition, using a reductive evolution simulation approach, they uncovered the absolutely essential proteins to support a minimal viable network.

“We were able to put together the information from the network biology as well as the protein structural biology,” said co-author Bernhard Palsson, Ph.D., a UC San Diego bioengineering professor who leads the Systems Biology Research Group. “This is the first time this has been accomplished. We are in a position to study microorganisms in much greater detail, including those that are important in health care and those that are of environmental concern.”

This work was funded by grants from the National Institute of General Medical Sciences and the Office of Biological and Environmental Research within the U.S. Department of Energy's Office of Science.

About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The institute ranks among the top four institutions nationally for NIH grant funding and among the top 25 organizations worldwide for its research impact. For the past decade (1999-2009), Burnham ranked first worldwide in the fields of biology and biochemistry for the impact of its research publications (defined by citations per publication), according to the Institute for Scientific Information.

Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit public benefit corporation.

About the University of California, San Diego
UC San Diego, one of the ten campuses in the world-renowned University of California system, is one of the top institutions in the nation for higher education and research, widely acknowledged for its local impact, national influence and global reach. Approximately one in four of the campus's 28,500 students are enrolled in the Jacobs School of Engineering, whose graduate program is ranked #11 in the country by U.S. News & World Report, which also ranks UC San Diego as the 7th best public university in the nation. The Jacobs School’s Bioengineering Department ranks #2 in the nation. The university's organized research units include the California Institute for Telecommunications and Information Technology (Calit2) and the Center for Research in Biological Systems (CRBS). The National Science Foundation ranks UC San Diego 6th in the nation in R&D expenditures at nearly $800 million in 2007-08, and the campus contributes more than $7.2 billion in direct and indirect spending and personal income each year to the California economy.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.