Abstract
BackgroundThe development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology. Integrated analysis of the resulting omic data sets has proved to be hard to achieve. Metabolic network reconstructions enable complex relationships amongst molecular components to be represented formally in a biologically relevant manner while respecting physical constraints. In silico models derived from such reconstructions can then be queried or interrogated through mathematical simulations. Proteomic profiling studies of the mature human erythrocyte have shown more proteins present related to metabolic function than previously thought; however the significance and the causal consequences of these findings have not been explored.ResultsErythrocyte proteomic data was used to reconstruct the most expansive description of erythrocyte metabolism to date, following extensive manual curation, assessment of the literature, and functional testing. The reconstruction contains 281 enzymes representing functions from glycolysis to cofactor and amino acid metabolism. Such a comprehensive view of erythrocyte metabolism implicates the erythrocyte as a potential biomarker for different diseases as well as a 'cell-based' drug-screening tool. The analysis shows that 94 erythrocyte enzymes are implicated in morbid single nucleotide polymorphisms, representing 142 pathologies. In addition, over 230 FDA-approved and experimental pharmaceuticals have enzymatic targets in the erythrocyte.ConclusionThe advancement of proteomic technologies and increased generation of high-throughput proteomic data have created the need for a means to analyze these data in a coherent manner. Network reconstructions provide a systematic means to integrate and analyze proteomic data in a biologically meaning manner. Analysis of the red cell proteome has revealed an unexpected level of complexity in the functional capabilities of human erythrocyte metabolism.
Highlights
The development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology
Results and Discussion iAB-RBC-283 is a proteomic based metabolic reconstruction and a biochemical knowledge-base, a functional integration of high-throughput biological data and existing experimentally verified biochemical erythrocyte knowledge that can be queried through simulations and calculations
# of conditions sharing same met. signature types of blood cells and inactive enzymes are passed down the erythrocyte differentiation lineage
Summary
The development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology. Whole-cell measurements can elucidate the genome sequence (genomics) as well as detect mRNA (transcriptomics), proteins (proteomics), and small metabolites (metabolomics) under a specific condition. Though these methods provide a broad coverage in determining cellular activities, little integrated functional analysis has been performed to date. Recon 1 has been adapted to study specific cells and tissues with the help of high-throughput data, including the human brain [8], liver [9,10], kidney [11], and alveolar macrophage [12]
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