Using the reconstructed genome-scale human metabolic network to study physiology and pathology

Abstract

Metabolism plays a key role in many major human diseases. Generation of high-throughput omics data has ushered in a new era of systems biology. Genome-scale metabolic network reconstructions provide a platform to interpret omics data in a biochemically meaningful manner. The release of the global human metabolic network, Recon 1, in 2007 has enabled new systems biology approaches to study human physiology, pathology and pharmacology. There are currently more than 20 publications that utilize Recon 1, including studies of cancer, diabetes, host-pathogen interactions, heritable metabolic disorders and off-target drug binding effects. In this mini-review, we focus on the reconstruction of the global human metabolic network and four classes of its application. We show that computational simulations for numerous pathologies have yielded clinically relevant results, many corroborated by existing or newly generated experimental data.

Figure 1

Recon 1 is a global human metabolic network reconstruction comprised of the known biochemical and physiologic data. A) Gene protein reaction associations can be represented in Boolean logic and are used to define a mechanistic genotype phenotype relationship. This is essential for determining phenotypes of genetic perturbations as well as understanding the underlying mechanisms of a particular phenotype. B) Recon 1 accounts for 3,311 metabolic reactions and their associated metabolites. The reactions in the network can be represented in a mathematical format called the stoichiometric matrix. C) Recon 1 is a thorough and very complex assessment of human metabolism accounting for over 1400 genes and 7 cellular compartments.

Figure 2

The four major applications of the global human metabolic network Recon 1. I) Utilizing high-throughput data, Recon 1 can be tailored to cell and tissue-specific networks. The process has been done both algorithmically and manually. II) Similarly, Recon 1 has been transformed into other mammalian reconstructions, particularly M. musculus. The high overlap of homologous genes in Recon 1 with similar mammals allows for reconstructing accurate mammalian models quickly. III) High-throughput data can be interpreted by mapping the data onto Recon 1’s metabolic network backbone. This process has been done to study pathological and drug-treated states. IV) Recon 1 can be used to simulate and predict phenotypes, providing biological clues to physiology and pathology as well as guiding experimental design.