Edinburgh Researchers Recreate Human Metabolism to Develop Better Drugs
29th November 2007

Many human diseases are caused by, or result in, an abnormal metabolic state, such as the high glucose concentration in blood of diabetes patients. Metabolic processes are also heavily involved in drug clearance. However metabolic pathways in humans are exceptionally numerous and complex, and much of the knowledge in this field is incomplete. It is important, therefore, to develop a better understanding of human metabolism and its relationship with diseases.

A group in Edinburgh, led by Professor Igor Goryanin, has developed a comprehensive reconstruction of human metabolism, the Edinburgh Metabolic Human Network (EMHN). This computational model consists of nearly 3000 metabolic reactions, organized into about 70 human-specific metabolic pathways according to their functional relationships. This in silico (computer) model of the reactions that take place in human cells allows researchers to test and develop potential new drugs in a realistic virtual environment. The high quality human metabolic network, when combined with the recent rapid developments in metabolomics technology, also has the potential to provide clinicians with a much more comprehensive assessment of a patient’s health status.

Although some human metabolic pathways such as glycolysis and urea cycle were discovered almost a hundred years ago, and many pathways have been extensively studied in biomedical journals and textbooks, a complete whole picture of human metabolic network is still missing. Some preliminary computational metabolic networks have been reconstructed from gene annotation information but they are generally neither of very high quality nor complete. The Edinburgh researchers manually reconstructed human metabolic network by integrating genome annotation information from different databases with metabolic reaction information from literature. This calibration of database information with experimental results reported in literature ensured the development of a high-quality metabolic network model. The high quality of the computationally reconstructed network, when compared with previously published networks, was achieved by integrating information from different databases, and by meticulous human curation.

The network includes 2823 reactions, organised into 66 pathways containing between 5 and 142 reactions. The whole set of pathways have been made available in SBML (systems biology markup language) a computer-readable format for representing models of biochemical reaction networks, which allows the user to quickly generate clear pathway maps using open source software.

A main objective of human metabolic network analysis is to see how it is related with human disease. More than 10 000 human genes (half of the whole genome) have been reported to related with one or more human diseases. Surprisingly, Goryanin’s group found that, in the human metabolic network, a much higher proportion of reactions are catalyzed by enzymes which are coded by disease related genes. The existence of multiple pathways for multiple substrates, however, provides flexibility to the organism and thus blocking one pathway is unlikely to damage it. In contrast, a product is synthesized in an organism often because it has some unique function important for the organism (as a structure molecule or a signal molecule). Hence, a failure in a product synthesis pathway can disrupt the whole system, causing disease. This finding confirms the importance of studying the effect of potential drugs on the entire metabolism, and not just on genes or gene products.

Ma et al, The Edinburgh human metabolic network reconstruction and its functional analysis. Mol Syst Biol. 2007; 3: 135

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