Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 30 August 2002:
Vol. 297. no. 5586, pp. 1551 - 1555
DOI: 10.1126/science.1073374
Prev | Table of Contents | Next

Reports

Hierarchical Organization of Modularity in Metabolic Networks

E. Ravasz,1 A. L. Somera,2 D. A. Mongru,2 Z. N. Oltvai,2* A.-L. Barabási1*

Spatially or chemically isolated functional modules composed of several cellular components and carrying discrete functions are considered fundamental building blocks of cellular organization, but their presence in highly integrated biochemical networks lacks quantitative support. Here, we show that the metabolic networks of 43 distinct organisms are organized into many small, highly connected topologic modules that combine in a hierarchical manner into larger, less cohesive units, with their number and degree of clustering following a power law. Within Escherichia coli, the uncovered hierarchical modularity closely overlaps with known metabolic functions. The identified network architecture may be generic to system-level cellular organization.

1 Department of Physics, University of Notre Dame, Notre Dame, IN 46556, USA.
2 Department of Pathology, Northwestern University, Chicago, IL 60611, USA.
*   To whom correspondence should be addressed. E-mail: zno008{at}northwestern.edu (Z.N.O.) and alb{at}nd.edu (A.-L.B.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Gene divergence and pathway duplication in the metabolic network of yeast and digital organisms.
P. Gerlee, T. Lundh, B. Zhang, and A. R. A. Anderson (2009)
J R Soc Interface 6, 1233-1245
   Abstract »    Full Text »    PDF »
Identification of genes involved in the same pathways using a Hidden Markov Model-based approach.
A. Senf and X.-w. Chen (2009)
Bioinformatics 25, 2945-2954
   Abstract »    Full Text »    PDF »
Reconstruct modular phenotype-specific gene networks by knowledge-driven matrix factorization.
X. Yang, Y. Zhou, R. Jin, and C. Chan (2009)
Bioinformatics 25, 2236-2243
   Abstract »    Full Text »    PDF »
Harnessing nature's toolbox: regulatory elements for synthetic biology.
P. M. Boyle and P. A. Silver (2009)
J R Soc Interface 6, S535-S546
   Abstract »    Full Text »    PDF »
Maximum-entropy network analysis reveals a role for tumor necrosis factor in peripheral nerve development and function.
P. S. Dhadialla, I. E. Ohiorhenuan, A. Cohen, and S. Strickland (2009)
PNAS 106, 12494-12499
   Abstract »    Full Text »    PDF »
Cluster Analysis for the Impact of Sickle Cell Disease on the Human Erythrocyte Protein Interactome.
L. P. Ammann and S. R. Goodman (2009)
Experimental Biology and Medicine 234, 703-711
   Abstract »    Full Text »    PDF »
A Network Modeling Approach to Analysis of the Th2 Memory Responses Underlying Human Atopic Disease.
A. Bosco, K. L. McKenna, M. J. Firth, P. D. Sly, and P. G. Holt (2009)
J. Immunol. 182, 6011-6021
   Abstract »    Full Text »    PDF »
Expression Quantitative Trait Loci Mapping With Multivariate Sparse Partial Least Squares Regression.
H. Chun and S. Keles (2009)
Genetics 182, 79-90
   Abstract »    Full Text »    PDF »
Gclust: trans-kingdom classification of proteins using automatic individual threshold setting.
N. Sato (2009)
Bioinformatics 25, 599-605
   Abstract »    Full Text »    PDF »
Insights into the Organization of Biochemical Regulatory Networks Using Graph Theory Analyses.
A. Ma'ayan (2009)
J. Biol. Chem. 284, 5451-5455
   Abstract »    Full Text »    PDF »
Bioinformatics Resources for the Study of Gene Regulation in Bacteria.
J. Collado-Vides, H. Salgado, E. Morett, S. Gama-Castro, V. Jimenez-Jacinto, I. Martinez-Flores, A. Medina-Rivera, L. Muniz-Rascado, M. Peralta-Gil, and A. Santos-Zavaleta (2009)
J. Bacteriol. 191, 23-31
   Full Text »    PDF »
Principles of transcriptional regulation and evolution of the metabolic system in E. coli.
A. S.N. Seshasayee, G. M. Fraser, M. M. Babu, and N. M. Luscombe (2009)
Genome Res. 19, 79-91
   Abstract »    Full Text »    PDF »
Modularity of cellular networks shows general center-periphery polarization.
A. E. Vinogradov (2008)
Bioinformatics 24, 2814-2817
   Abstract »    Full Text »    PDF »
Evolutionary Constraint and Adaptation in the Metabolic Network of Drosophila.
A. J. Greenberg, S. R. Stockwell, and A. G. Clark (2008)
Mol. Biol. Evol. 25, 2537-2546
   Abstract »    Full Text »    PDF »
The Protein Interaction Network of the Epithelial Junctional Complex: A System-Level Analysis.
L. Paris and G. Bazzoni (2008)
Mol. Biol. Cell 19, 5409-5421
   Abstract »    Full Text »    PDF »
Phylogenetic distances are encoded in networks of interacting pathways.
A. Mazurie, D. Bonchev, B. Schwikowski, and G. A. Buck (2008)
Bioinformatics 24, 2579-2585
   Abstract »    Full Text »    PDF »
Predicting gene targets of perturbations via network-based filtering of mRNA expression compendia.
E. J. Cosgrove, Y. Zhou, T. S. Gardner, and E. D. Kolaczyk (2008)
Bioinformatics 24, 2482-2490
   Abstract »    Full Text »    PDF »
Targeting the Human Cancer Pathway Protein Interaction Network by Structural Genomics.
Y. J. Huang, D. Hang, L. J. Lu, L. Tong, M. B. Gerstein, and G. T. Montelione (2008)
Mol. Cell. Proteomics 7, 2048-2060
   Abstract »    Full Text »    PDF »
Models and computational strategies linking physiological response to molecular networks from large-scale data.
F. Ortega, K. Sameith, N. Turan, R. Compton, V. Trevino, M. Vannucci, and F. Falciani (2008)
Phil Trans R Soc A 366, 3067-3089
   Abstract »    Full Text »    PDF »
Cascading failure and robustness in metabolic networks.
A. G. Smart, L. A. N. Amaral, and J. M. Ottino (2008)
PNAS 105, 13223-13228
   Abstract »    Full Text »    PDF »
Automatic decomposition of kinetic models of signaling networks minimizing the retroactivity among modules.
J. Saez-Rodriguez, S. Gayer, M. Ginkel, and E. D. Gilles (2008)
Bioinformatics 24, i213-i219
   Abstract »    Full Text »    PDF »
VisANT: an integrative framework for networks in systems biology.
Z. Hu, E. S. Snitkin, and C. DeLisi (2008)
Brief Bioinform 9, 317-325
   Abstract »    Full Text »    PDF »
Microbial genotype-phenotype mapping by class association rule mining.
M. Tamura and P. D'haeseleer (2008)
Bioinformatics 24, 1523-1529
   Abstract »    Full Text »    PDF »
Modularity of stress response evolution.
A. H. Singh, D. M. Wolf, P. Wang, and A. P. Arkin (2008)
PNAS 105, 7500-7505
   Abstract »    Full Text »    PDF »
Automated extraction of meaningful pathways from quantitative proteomics data.
J. Noirel, S. Y. Ow, G. Sanguinetti, A. Jaramillo, and P. C. Wright (2008)
Brief Funct Genomic Proteomic
   Abstract »    Full Text »    PDF »
Arginine Biosynthesis in Escherichia coli: EXPERIMENTAL PERTURBATION AND MATHEMATICAL MODELING.
M. Caldara, G. Dupont, F. Leroy, A. Goldbeter, L. De Vuyst, and R. Cunin (2008)
J. Biol. Chem. 283, 6347-6358
   Abstract »    Full Text »    PDF »
A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging.
J. A. Miller, M. C. Oldham, and D. H. Geschwind (2008)
J. Neurosci. 28, 1410-1420
   Abstract »    Full Text »    PDF »
Practical and theoretical advances in predicting the function of a protein by its phylogenetic distribution.
P. R Kensche, V. van Noort, B. E Dutilh, and M. A Huynen (2008)
J R Soc Interface 5, 151-170
   Abstract »    Full Text »    PDF »
Spontaneous emergence of modularity in cellular networks.
R. V Sole and S. Valverde (2008)
J R Soc Interface 5, 129-133
   Abstract »    Full Text »    PDF »
Multidimensional annotation of the Escherichia coli K-12 genome.
P. D. Karp, I. M. Keseler, A. Shearer, M. Latendresse, M. Krummenacker, S. M. Paley, I. Paulsen, J. Collado-Vides, S. Gama-Castro, M. Peralta-Gil, et al. (2007)
Nucleic Acids Res. 35, 7577-7590
   Abstract »    Full Text »    PDF »
Extracting the hierarchical organization of complex systems.
M. Sales-Pardo, R. Guimera, A. A. Moreira, and L. A. N. Amaral (2007)
PNAS 104, 15224-15229
   Abstract »    Full Text »    PDF »
Constraint-based functional similarity of metabolic genes: going beyond network topology.
O. Rokhlenko, T. Shlomi, R. Sharan, E. Ruppin, and R. Y. Pinter (2007)
Bioinformatics 23, 2139-2146
   Abstract »    Full Text »    PDF »
The Product Space Conditions the Development of Nations.
C. A. Hidalgo, B. Klinger, A.-L. Barabasi, and R. Hausmann (2007)
Science 317, 482-487
   Abstract »    Full Text »    PDF »
VisANT 3.0: new modules for pathway visualization, editing, prediction and construction.
Z. Hu, D. M. Ng, T. Yamada, C. Chen, S. Kawashima, J. Mellor, B. Linghu, M. Kanehisa, J. M. Stuart, and C. DeLisi (2007)
Nucleic Acids Res. 35, W625-W632
   Abstract »    Full Text »    PDF »
Annotating gene function by combining expression data with a modular gene network.
M. Shiga, I. Takigawa, and H. Mamitsuka (2007)
Bioinformatics 23, i468-i478
   Abstract »    Full Text »    PDF »
Transcription factor modularity in a gene-centered C. elegans core neuronal protein-DNA interaction network.
V. Vermeirssen, M. I. Barrasa, C. A. Hidalgo, J. A. B. Babon, R. Sequerra, L. Doucette-Stamm, A.-L. Barabasi, and A. J.M. Walhout (2007)
Genome Res. 17, 1061-1071
   Abstract »    Full Text »    PDF »
A network-based method for target selection in metabolic networks.
R. Guimera, M. Sales-Pardo, and L.A.N. Amaral (2007)
Bioinformatics 23, 1616-1622
   Abstract »    Full Text »    PDF »
Quantifying fitness distributions and phenotypic relationships in recombinant yeast populations.
E. O. Perlstein, E. J. Deeds, O. Ashenberg, E. I. Shakhnovich, and S. L. Schreiber (2007)
PNAS 104, 10553-10558
   Abstract »    Full Text »    PDF »
The human disease network.
K.-I. Goh, M. E. Cusick, D. Valle, B. Childs, M. Vidal, and A.-L. Barabasi (2007)
PNAS 104, 8685-8690
   Abstract »    Full Text »    PDF »
Biological impacts and context of network theory.
E. Almaas (2007)
J. Exp. Biol. 210, 1548-1558
   Abstract »    Full Text »    PDF »
Epstein-Barr virus and virus human protein interaction maps.
M. A. Calderwood, K. Venkatesan, L. Xing, M. R. Chase, A. Vazquez, A. M. Holthaus, A. E. Ewence, N. Li, T. Hirozane-Kishikawa, D. E. Hill, et al. (2007)
PNAS 104, 7606-7611
   Abstract »    Full Text »    PDF »
Clustering by common friends finds locally significant proteins mediating modules.
B. Andreopoulos, A. An, X. Wang, M. Faloutsos, and M. Schroeder (2007)
Bioinformatics 23, 1124-1131
   Abstract »    Full Text »    PDF »
Modular organization of protein interaction networks.
F. Luo, Y. Yang, C.-F. Chen, R. Chang, J. Zhou, and R. H. Scheuermann (2007)
Bioinformatics 23, 207-214
   Abstract »    Full Text »    PDF »
Network neighborhood analysis with the multi-node topological overlap measure.
A. Li and S. Horvath (2007)
Bioinformatics 23, 222-231
   Abstract »    Full Text »    PDF »
Resolution limit in community detection.
S. Fortunato and M. Barthelemy (2007)
PNAS 104, 36-41
   Abstract »    Full Text »    PDF »
The interaction networks of structured RNAs.
A. Lescoute and E. Westhof (2006)
Nucleic Acids Res. 34, 6587-6604
   Abstract »    Full Text »    PDF »
Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Reverse engineering gene networks to identify key drivers of complex disease phenotypes.
E. E. Schadt and P. Y. Lum (2006)
J. Lipid Res. 47, 2601-2613
   Abstract »    Full Text »    PDF »
Conservation and evolution of gene coexpression networks in human and chimpanzee brains.
M. C. Oldham, S. Horvath, and D. H. Geschwind (2006)
PNAS 103, 17973-17978
   Abstract »    Full Text »    PDF »
Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Network perspectives of cardiovascular metabolism.
J. N. Weiss, L. Yang, and Z. Qu (2006)
J. Lipid Res. 47, 2355-2366
   Abstract »    Full Text »    PDF »
A Brief History of Systems Biology: "Every object that biology studies is a system of systems." Francois Jacob (1974)..
A. Trewavas (2006)
PLANT CELL 18, 2420-2430
   Full Text »    PDF »
Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.
P. S. Gargalovic, M. Imura, B. Zhang, N. M. Gharavi, M. J. Clark, J. Pagnon, W.-P. Yang, A. He, A. Truong, S. Patel, et al. (2006)
PNAS 103, 12741-12746
   Abstract »    Full Text »    PDF »
Mathematical Modeling of Polyamine Metabolism in Mammals.
C. Rodriguez-Caso, R. Montanez, M. Cascante, F. Sanchez-Jimenez, and M. A. Medina (2006)
J. Biol. Chem. 281, 21799-21812
   Abstract »    Full Text »    PDF »
Observing local and global properties of metabolic pathways: 'load points' and 'choke points' in the metabolic networks.
S. A. Rahman and D. Schomburg (2006)
Bioinformatics 22, 1767-1774
   Abstract »    Full Text »    PDF »
Gene-balanced duplications, like tetraploidy, provide predictable drive to increase morphological complexity.
M. Freeling and B. C. Thomas (2006)
Genome Res. 16, 805-814
   Abstract »    Full Text »    PDF »
Adaptive functional differentiation of dendritic cells: integrating the network of extra- and intracellular signals.
T. Luft, E. Rodionova, E. Maraskovsky, M. Kirsch, M. Hess, C. Buchholtz, M. Goerner, M. Schnurr, R. Skoda, and A. D. Ho (2006)
Blood 107, 4763-4769
   Abstract »    Full Text »    PDF »
Efficient estimation of graphlet frequency distributions in protein-protein interaction networks.
N. Przulj, D. G. Corneil, and I. Jurisica (2006)
Bioinformatics 22, 974-980
   Abstract »    Full Text »    PDF »
The origins and evolution of functional modules: lessons from protein complexes.
J. B Pereira-Leal, E. D Levy, and S. A Teichmann (2006)
Phil Trans R Soc B 361, 507-517
   Abstract »    Full Text »    PDF »
The effect of oxygen on biochemical networks and the evolution of complex life..
J. Raymond and D. Segre (2006)
Science 311, 1764-1767
   Abstract »    Full Text »    PDF »
Identification and analysis of evolutionarily cohesive functional modules in protein networks.
M. Campillos, C. von Mering, L. J. Jensen, and P. Bork (2006)
Genome Res. 16, 374-382
   Abstract »    Full Text »    PDF »
Copying nodes versus editing links: the source of the difference between genetic regulatory networks and the WWW.
Y. Louzoun, L. Muchnik, and S. Solomon (2006)
Bioinformatics 22, 581-588
   Abstract »    Full Text »    PDF »
Sexual reproduction reshapes the genetic architecture of digital organisms.
D. Misevic, C. Ofria, and R. E Lenski (2006)
Proc R Soc B 273, 457-464
   Abstract »    Full Text »    PDF »
From The Cover: A simple physical model for scaling in protein-protein interaction networks.
E. J. Deeds, O. Ashenberg, and E. I. Shakhnovich (2006)
PNAS 103, 311-316
   Abstract »    Full Text »    PDF »
Topological and Functional Discovery in a Gene Coexpression Meta-Network of Gastric Cancer.
A. Aggarwal, D. Li Guo, Y. Hoshida, S. Tsan Yuen, K.-M. Chu, S. So, A. Boussioutas, X. Chen, D. Bowtell, H. Aburatani, et al. (2006)
Cancer Res. 66, 232-241
   Abstract »    Full Text »    PDF »
Scale-free networks in cell biology.
R. Albert (2005)
J. Cell Sci. 118, 4947-4957
   Abstract »    Full Text »    PDF »
A Novel Approach for Nontargeted Data Analysis for Metabolomics. Large-Scale Profiling of Tomato Fruit Volatiles.
Y. Tikunov, A. Lommen, C.H. R. de Vos, H. A. Verhoeven, R. J. Bino, R. D. Hall, and A. G. Bovy (2005)
Plant Physiology 139, 1125-1137
   Abstract »    Full Text »    PDF »
The "robust yet fragile" nature of the Internet.
J. C. Doyle, D. L. Alderson, L. Li, S. Low, M. Roughan, S. Shalunov, R. Tanaka, and W. Willinger (2005)
PNAS 102, 14497-14502
   Abstract »    Full Text »    PDF »
A network of transcriptionally coordinated functional modules in Saccharomyces cerevisiae.
A. A. Petti and G. M. Church (2005)
Genome Res. 15, 1298-1306
   Abstract »    Full Text »    PDF »
Embracing Complexity, Inching Closer to Reality.
E. E. Schadt, A. Sachs, and S. Friend (2005)
Sci. STKE 2005, pe40
   Abstract »    Full Text »    PDF »
The DNA damage response and patient safety: engaging our molecular biology-oriented colleagues.
K. Pukk and D. C. Aron (2005)
Int. J. Qual. Health Care 17, 363-367
   Abstract »    Full Text »    PDF »
Functional annotation from predicted protein interaction networks.
J. McDermott, R. Bumgarner, and R. Samudrala (2005)
Bioinformatics 21, 3217-3226
   Abstract »    Full Text »    PDF »
Scale-Freeness and Biological Networks.
M. Arita (2005)
J. Biochem. 138, 1-4
   Abstract »    Full Text »    PDF »
VisANT: data-integrating visual framework for biological networks and modules.
Z. Hu, J. Mellor, J. Wu, T. Yamada, D. Holloway, and C. DeLisi (2005)
Nucleic Acids Res. 33, W352-W357
   Abstract »    Full Text »    PDF »
Metabolic Engineering in the -omics Era: Elucidating and Modulating Regulatory Networks.
G. N. Vemuri and A. A. Aristidou (2005)
Microbiol. Mol. Biol. Rev. 69, 197-216
   Abstract »    Full Text »    PDF »
Intracellular Signaling: Spatial and Temporal Control.
I. I. Moraru and L. M. Loew (2005)
Physiology 20, 169-179
   Abstract »    Full Text »    PDF »
Correlation between gene expression profiles and protein-protein interactions within and across genomes.
N. Bhardwaj and H. Lu (2005)
Bioinformatics 21, 2730-2738
   Abstract »    Full Text »    PDF »
Genomes, phylogeny, and evolutionary systems biology.
M. Medina (2005)
PNAS 102, 6630-6635
   Abstract »    Full Text »    PDF »
Novel specificities emerge by stepwise duplication of functional modules.
J. B. Pereira-Leal and S. A. Teichmann (2005)
Genome Res. 15, 552-559
   Abstract »    Full Text »    PDF »
Local correlation of expression profiles with gene annotations--proof of concept for a general conciliatory method.
F. R. Pinto, L. A. Cowart, Y. A. Hannun, B. Rohrer, and J. S. Almeida (2005)
Bioinformatics 21, 1037-1045
   Abstract »    Full Text »    PDF »
Comparative Genomics of Centrality and Essentiality in Three Eukaryotic Protein-Interaction Networks.
M. W. Hahn and A. D. Kern (2005)
Mol. Biol. Evol. 22, 803-806
   Abstract »    Full Text »    PDF »
Lasting impressions: Motifs in protein-protein maps may provide footprints of evolutionary events.
J. J. Rice, A. Kershenbaum, and G. Stolovitzky (2005)
PNAS 102, 3173-3174
   Full Text »    PDF »
The topological relationship between the large-scale attributes and local interaction patterns of complex networks.
A. Vazquez, R. Dobrin, D. Sergi, J.-P. Eckmann, Z. N. Oltvai, and A.-L. Barabasi (2004)
PNAS 101, 17940-17945
   Abstract »    Full Text »    PDF »
Computational modeling reveals how interplay between components of a GTPase-cycle module regulates signal transduction.
S. J. Bornheimer, M. R. Maurya, M. G. Farquhar, and S. Subramaniam (2004)
PNAS 101, 15899-15904
   Abstract »    Full Text »    PDF »
Conservation and Coevolution in the Scale-Free Human Gene Coexpression Network.
I. K. Jordan, L. Marino-Ramirez, Y. I. Wolf, and E. V. Koonin (2004)
Mol. Biol. Evol. 21, 2058-2070
   Abstract »    Full Text »    PDF »
The interactome as a tree--an attempt to visualize the protein-protein interaction network in yeast.
H. Lu, X. Zhu, H. Liu, G. Skogerbo, J. Zhang, Y. Zhang, L. Cai, Y. Zhao, S. Sun, J. Xu, et al. (2004)
Nucleic Acids Res. 32, 4804-4811
   Abstract »    Full Text »    PDF »
GENEVESTIGATOR. Arabidopsis Microarray Database and Analysis Toolbox.
P. Zimmermann, M. Hirsch-Hoffmann, L. Hennig, and W. Gruissem (2004)
Plant Physiology 136, 2621-2632
   Abstract »    Full Text »    PDF »
Polyanions and the Proteome.
L. S. Jones, B. Yazzie, and C. R. Middaugh (2004)
Mol. Cell. Proteomics 3, 746-769
   Abstract »    Full Text »    PDF »
Design of a directed molecular network.
G. Ashkenasy, R. Jagasia, M. Yadav, and M. R. Ghadiri (2004)
PNAS 101, 10872-10877
   Abstract »    Full Text »    PDF »
Differential metabolic networks unravel the effects of silent plant phenotypes.
W. Weckwerth, M. E. Loureiro, K. Wenzel, and O. Fiehn (2004)
PNAS 101, 7809-7814
   Abstract »    Full Text »    PDF »
Universality and flexibility in gene expression from bacteria to human.
H. R. Ueda, S. Hayashi, S. Matsuyama, T. Yomo, S. Hashimoto, S. A. Kay, J. B. Hogenesch, and M. Iino (2004)
PNAS 101, 3765-3769
   Abstract »    Full Text »    PDF »
Defining and identifying communities in networks.
F. Radicchi, C. Castellano, F. Cecconi, V. Loreto, and D. Parisi (2004)
PNAS 101, 2658-2663
   Abstract »    Full Text »    PDF »
Revealing modularity and organization in the yeast molecular network by integrated analysis of highly heterogeneous genomewide data.
A. Tanay, R. Sharan, M. Kupiec, and R. Shamir (2004)
PNAS 101, 2981-2986
   Abstract »    Full Text »    PDF »
Comparative Analysis of Protein Domain Organization.
Y. Ye and A. Godzik (2004)
Genome Res. 14, 343-353
   Abstract »    Full Text »    PDF »
Control of Yeast Filamentous-Form Growth by Modules in an Integrated Molecular Network.
S. Prinz, I. Avila-Campillo, C. Aldridge, A. Srinivasan, K. Dimitrov, A. F. Siegel, and T. Galitski (2004)
Genome Res. 14, 380-390
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)