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BIOLOGICAL SCIENCES / APPLIED BIOLOGICAL SCIENCES
Global reconstruction of the human metabolic network based on genomic and bibliomic data

Natalie C. Duarte, Scott A. Becker, Neema Jamshidi, Ines Thiele, Monica L. Mo, Thuy D. Vo, Rohith Srivas, and Bernhard Ø. Palsson^*

Bioengineering Department, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412

Communicated by Shu Chien, University of California at San Diego, La Jolla, CA, December 5, 2006 (received for review October 9, 2006)

Metabolism is a vital cellular process, and its malfunction is a major contributor to human disease. Metabolic networks are complex and highly interconnected, and thus systems-level computational approaches are required to elucidate and understand metabolic genotype–phenotype relationships. We have manually reconstructed the global human metabolic network based on Build 35 of the genome annotation and a comprehensive evaluation of >50 years of legacy data (i.e., bibliomic data). Herein we describe the reconstruction process and demonstrate how the resulting genome-scale (or global) network can be used (i) for the discovery of missing information, (ii) for the formulation of an in silico model, and (iii) as a structured context for analyzing high-throughput biological data sets. Our comprehensive evaluation of the literature revealed many gaps in the current understanding of human metabolism that require future experimental investigation. Mathematical analysis of network structure elucidated the implications of intracellular compartmentalization and the potential use of correlated reaction sets for alternative drug target identification. Integrated analysis of high-throughput data sets within the context of the reconstruction enabled a global assessment of functional metabolic states. These results highlight some of the applications enabled by the reconstructed human metabolic network. The establishment of this network represents an important step toward genome-scale human systems biology.

constraint based | metabolism | model | systems biology

Conflict of interest statement: N.C.D., S.A.B., N.J., I.T., M.L.M., T.D.V., R.S., and B.Ø.P. and the University of California at San Diego disclose potential financial conflict of interest related to U.S. Patent Application (Pub. No. 20040029149), published on February 12, 2004.

This article contains supporting information online at www.pnas.org/cgi/content/full/0610772104/DC1.

*To whom correspondence should be addressed. E-mail: palsson{at}ucsd.edu

© 2007 by The National Academy of Sciences of the USA

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