Applications of genome-scale metabolic reconstructions

Abstract

The availability and utility of genome-scale metabolic reconstructions have exploded since the first genome-scale reconstruction was published a decade ago. Reconstructions have now been built for a wide variety of organisms, and have been used toward five major ends: (1) contextualization of high-throughput data, (2) guidance of metabolic engineering, (3) directing hypothesis-driven discovery, (4) interrogation of multi-species relationships, and (5) network property discovery. In this review, we examine the many uses and future directions of genome-scale metabolic reconstructions, and we highlight trends and opportunities in the field that will make the greatest impact on many fields of biology.

Figure 1

Reconstruction statistics. The cumulative number of metabolic GENREs published over the past decade is shown in (A). (B–D) Histograms of the number of metabolic GENREs containing varying numbers of genes (B), metabolites (C), and reactions (D). (E) Histogram of the number of reconstructions published per species. All histograms display prokaryotic (green) and eukaryotic (brown) statistics. ^*Yeast, S. cerevisiae; Human^1,2, human reconstructions (Duarte et al, 2007; Ma et al, 2007).

Figure 2

Uses of metabolic GENREs. The building and analysis of metabolic GENREs are shown in the left panels, and the five categories of uses of metabolic GENREs as highlighted in this paper are described in the right set of panels. Each panel on the right includes a representative example from literature.

Figure 3

Phylogenetic tree of reconstructed species. This figure shows a phylogenetic tree of all species for which metabolic GENREs have been built. Sections are colored by superkingdom, and phyla are noted on the outer ring of the tree. The phylogenetic tree was generated using semi-automated software at http://itol.embl.de/ (Ciccarelli et al, 2006), and phyla were determined using the NCBI taxonomy browser.

Figure 4

Analyses of metabolic GENREs. A heat map of studies that have been published for all reconstructed species (y-axis) using a variety of analysis techniques (x-axis). Analyses are broken into two categories: ‘model validation,' indicating the use of a technique in a publication of a new metabolic GENRE to establish the validity of a model, and ‘model-guided discovery,' indicating the use of a technique either in an original metabolic GENRE publication or in a follow-up study to perform one of the five types of studies outlined in this paper. Species are grouped according to the most relevant broad category to which the metabolic GENRE has been applied. Colors in the heat map indicate the number of publications performing the given analysis on a metabolic GENRE of the organism. References for each species in the figure are as follows: M. barkeri (Becker et al, 2006; Feist et al, 2006; Kun et al, 2008; Mahadevan and Lovley, 2008; Wright and Wagner, 2008), R. etli (Resendis-Antonio et al, 2007), Synechocystis sp. (Kun et al, 2008), M. genitalium (Suthers et al, 2009), H. sapiens (Duarte et al, 2007; Ma et al, 2007; Vo et al, 2007; Shlomi et al, 2008, 2009; Veeramani and Bader, 2009), M. musculus (Sheikh et al, 2005; Quek and Nielsen, 2008; Selvarasu et al, 2009), A. thaliana (Radrich et al, http://hdl.handle.net/10101/npre.2009.3309.1), H. influenza (Edwards and Palsson, 1999; Papin et al, 2002a; Papin et al, 2002b; Price et al, 2002; Price et al, 2003; Schilling and Palsson, 2000), H. pylori (Price et al, 2002, 2003; Schilling et al, 2002; Papin et al, 2002b; Thiele et al, 2005; Becker et al, 2006; Guimera et al, 2007; Kun et al, 2008; Wright and Wagner, 2008), M. tuberculosis (Beste et al, 2009; Beste et al, 2007; Jamshidi and Palsson, 2007; Kun et al, 2008), N. meningitides (Baart et al, 2007a, 2007b), P. aeruginosa (Oberhardt et al, 2008), S. aureus (Becker and Palsson, 2005; Becker et al, 2006; Heinemann et al, 2005; Kun et al, 2008; Samal et al, 2006), S. typhimurium (Abuoun et al, 2009; Raghunathan et al, 2009), Y. pestis (Navid and Almaas, 2009), P. gingivalis (Mazumdar et al, 2009), L. major (Chavali et al, 2008b), C. reinhardtii (Boyle and Morgan, 2009), H. salinarum (Gonzalez et al, 2008), B. subtilis (Oh et al, 2007; Henry et al, 2009a, 2009b), C. acetobutylicum (Lee et al, 2008a; Senger and Papoutsakis, 2008a), C. glutamicum (Kjeldsen and Nielsen, 2009; Shinfuku et al, 2009), L. plantarum (Teusink et al, 2006, 2009; Stevens et al, 2008), L. lactis (Oliveira et al, 2005; Kun et al, 2008), M. succiniciproducens (Kim et al, 2007; Song et al, 2008; Lee et al, 2008c), P. putida (Nogales et al, 2008; Puchalka et al, 2008), S. coelicolor (Borodina et al, 2005; Hiratsuka et al, 2008; Kun et al, 2008), S. thermophilus (Pastink et al, 2009), A. nidulans (David et al, 2006, 2008; Panagiotou et al, 2008, 2009), A. niger (Andersen et al, 2008; Thykaer et al, 2009), A. oryzae (Vongsangnak et al, 2008), S. cerevisiae (Famili et al, 2003; Forster et al, 2003; Daran-Lapujade et al, 2004; Duarte et al, 2004; Prinz et al, 2004; Kuepfer et al, 2005; Patil and Nielsen, 2005; Becker et al, 2006; Cakir et al, 2006; Herrgard et al, 2006, 2008; Raghevendran et al, 2006; Samal et al, 2006; Usaite et al, 2006; Bundy et al, 2007; Harrison et al, 2007; Rokhlenko et al, 2007; Shlomi et al, 2007; Chechik et al, 2008; Deutscher et al, 2008; Kun et al, 2008; Mahadevan and Lovley, 2008; Nookaew et al, 2008; Notebaart et al, 2008; Wright and Wagner, 2008; Zelle et al, 2008; Cimini et al, 2009; Mintz-Oron et al, 2009; Mo et al, 2009), A. baylyi (Durot et al, 2008), G. sulfurreducens (Izallalen et al, 2008; Kun et al, 2008; Leang et al, 2009; Mahadevan et al, 2006; Mahadevan and Lovley, 2008; Risso et al, 2008; Scheibe et al, 2009; Segura et al, 2008), G. metallireducens (Sun et al, 2009).