Global reconstruction of the human metabolic network based on genomic and bibliomic data

Duarte et al. 10.1073/pnas.0610772104.

Supporting Information

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SI Figure 5
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Fig. 5. An outline of the development, dissemination, and possible applications of Homo sapiens Recon 1. Initial component lists were derived from the genome annotation and pathway databases. Iterative rounds of manual reconstruction and gap analysis were required to form a functional, predictive model. The results of this procedure is H. sapiens Recon 1, a biochemically, genetically, and genomically integrated (BiGG) database whose contents are freely available. Recon 1 has many potential applications, many of which may aid in the elucidation and treatment of human disease.

Fig. 6. Quality control procedure for network validation. After each round of reconstruction, the stoichiometric matrix (SI Tables 2-4) was formulated for functional validation. Changes proposed by the simulation were recorded in a spreadsheet and approved or rejected by the reconstruction team. Additions were immediately incorporated into a new open edition of the network, whereas deletions were handled by the debugging leader to ensure they did not disrupt any other functionalities. The model content was fixed (or versioned) after each round of reconstruction and debugging.

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Fig. 7. Map of amino acid metabolism in H. sapiens Recon 1.

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Fig. 8. Map of carbohydrate metabolism in H. sapiens Recon 1.

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Fig. 9. Map of energy metabolism in H. sapiens Recon 1.

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Fig. 10. Map of glycan metabolism in H. sapiens Recon 1.

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Fig. 11. Map of lipid metabolism in H. sapiens Recon 1.

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Fig. 12. Map of nucleotide metabolism in H. sapiens Recon 1.

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Fig. 13. Map of secondary metabolism in H. sapiens Recon 1.

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Fig. 14. Map of vitamin and cofactor metabolism in H. sapiens Recon 1.

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Fig. 15. Metabolic knowledge landscape for chondroitin sulfate degradation. Proteoglycans presumably undergo initial cleavage extracellularly, producing short peptides with single chondroitin sulfate chains (cspg_b). These chains are then endocytosed and further degraded by endosomal endoglycosidases to produce free chondroitin sulfate chains (cs_b). No biological evidence supporting this mechanism has been identified yet. Note that the peptide by-product (Ser-Gly/Ala-X-Gly) is a "dead-end" metabolite that is produced but not consumed. Final degradation of the core tetrasaccharide linkage (LINKDEG2ly) was inferred based on enzymes identified in rabbit. Reactions are color-coded by confidence scores: 3 - red, 2 - green, 1 - blue. Reaction, metabolite, and gene abbreviations are defined in SI Tables 5, 7, and 8, respectively.

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Fig. 16. Metabolic knowledge landscape for glyoxylate and dicarboxylate metabolism. Category II pathways typically have a combination of well-known functions, such as the degradation of glyoxylate (glx) to glycine (gly) in normal physiological conditions and overproduction of oxalate (oxa) in oxalosis, and those that are poorly understood, such as the feedback of glycolate intermediate hydroxypyruvate (hpyr) to glycolysis. Reactions are color-coded by confidence scores: 3 - red, 2 - green, 1 - blue. Reaction, metabolite, and gene abbreviations are defined in SI Tables 5, 7, and 8, respectively.

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Fig. 17. Metabolic knowledge landscape for vitamin C metabolism. The degradation of 2,3-dioxo-L-gulonate (23doguln) to L-xylonate (xylnt), L-lyxonate (lyxnt), and L-threonate (thrnt) are supported by physiological evidence, but the exact reaction mechanisms in which these four- and five-carbon sugar acids are converted to glycolytic intermediates could not be identified in the literature. Reactions are color-coded by confidence scores: 3 - red, 2 - green, 1 - blue. Reaction, metabolite, and gene abbreviations are defined in SI Tables 5, 7, and 8, respectively.

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Fig. 18. Metabolic knowledge landscape for ubiquinone biosynthesis. Ubiquinone biosynthesis is an example of a Category III pathway, in which many enzymatic reactions lack genetic or biochemical evidence. Reactions are color-coded by confidence scores: 3 - red, 2 - green, 1 - blue. Reaction, metabolite, and gene abbreviations are defined in SI Tables 5, 7, and 8, respectively.

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Fig. 19. High-resolution version of Fig. 3A. Reaction and metabolite abbreviations are defined in SI Tables 5 and 7, respectively.

Fig. 20. High-resolution version of Fig. 3B. Reaction and metabolite abbreviations are defined in SI Tables 5 and 7, respectively.

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Fig. 21. High-resolution version of Fig. 4. Reaction and metabolite abbreviations are defined in SI Tables 5 and 7, respectively.

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Fig. 22. Compartmentalization and metabolite connectivity of up-regulated and down-regulated reaction networks postgastric bypass. Distinct reaction networks were defined based on gene expression ratios in the gastric bypass study. Most down-regulated reactions (424 total) relate to mitochondrial bioenergetics and peroxisomal oxidation whereas up-regulated reactions (432 total) reflect a shift toward amino acid-sodium co-transport and lysosomal degradation. See SI Table 7 for metabolite abbreviations. Transport - other: metabolite exchange between the cytoplasm and nucleus, lysosome, endoplasmic reticulum, Golgi, and peroxisome. ER - endoplasmic reticulum.