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See detailThe Virtual Metabolic Human database: integrating human and gut microbiome metabolism with nutrition and disease
Noronha, Alberto UL; Modamio Chamarro, Jennifer UL; Jarosz, Yohan UL et al

in Nucleic Acids Research (2018)

A multitude of factors contribute to complex diseases and can be measured with ‘omics’ methods. Databases facilitate data interpretation for underlying mechanisms. Here, we describe the Virtual Metabolic ... [more ▼]

A multitude of factors contribute to complex diseases and can be measured with ‘omics’ methods. Databases facilitate data interpretation for underlying mechanisms. Here, we describe the Virtual Metabolic Human (VMH, www.vmh.life) database encapsulating current knowledge of human metabolism within five interlinked resources ‘Human metabolism’, ‘Gut microbiome’, ‘Disease’, ‘Nutrition’, and ‘ReconMaps’. The VMH captures 5180 unique metabolites, 17 730 unique reactions, 3695 human genes, 255 Mendelian diseases, 818 microbes, 632 685 microbial genes and 8790 food items. The VMH’s unique features are (i) the hosting of the metabolic reconstructions of human and gut microbes amenable for metabolic modeling; (ii) seven human metabolic maps for data visualization; (iii) a nutrition designer; (iv) a user-friendly webpage and application-programming interface to access its content; (v) user feedback option for community engagement and (vi) the connection of its entities to 57 other web resources. The VMH represents a novel, interdisciplinary database for data interpretation and hypothesis generation to the biomedical community. [less ▲]

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See detailMembrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease
Sahoo, Swagatika UL; Aurich, Maike Kathrin UL; Jonsson, Jon et al

in Frontiers in Physiology (2014), 5

Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network ... [more ▼]

Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions. [less ▲]

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See detailModeling the effects of commonly used drugs on human metabolism
Sahoo, Swagatika UL; Haraldsdottir, Hulda UL; Fleming, Ronan MT UL et al

in FEBS Journal (2014)

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein ... [more ▼]

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives, immunosuppressants, and analgesics. This reconstruction captures in detail our current understanding of their absorption, intra-cellular distribution, metabolism, and elimination. We combined this drug module with the most comprehensive reconstruction of human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803 metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the overall drug metabolism of these compounds, we investigated effects of dietary composition and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main findings include (i) shift in dietary patterns significantly affect statins and acetaminophen metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can be explained by several common metabolic and transport pathways other than the previously established CYP3A4 connection. This work holds the potential for studying adverse drug reactions and designing patient-specific therapies. [less ▲]

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See detailPredicting the impact of diet and enzymopathies on human small intestinal epithelial cells
Sahoo, Swagatika UL; Thiele, Ines UL

in Human Molecular Genetics (2013), 22(13), 2705-22

Small intestinal epithelial cells (sIECs) have a significant share in whole body metabolism as they perform enzymatic digestion and absorption of nutrients. Furthermore, the diet plays a key role in a ... [more ▼]

Small intestinal epithelial cells (sIECs) have a significant share in whole body metabolism as they perform enzymatic digestion and absorption of nutrients. Furthermore, the diet plays a key role in a number of complex diseases including obesity and diabetes. The impact of diet and altered genetic backgrounds on human metabolism may be studied by using computational modeling. A metabolic reconstruction of human sIECs was manually assembled using the literature. The resulting sIEC model was subjected to two different diets to obtain condition-specific metabolic models. Fifty defined metabolic tasks evaluated the functionalities of these models, along with the respective secretion profiles, which distinguished between impacts of different dietary regimes. Under the average American diet, the sIEC model resulted in higher secretion flux for metabolites implicated in metabolic syndrome. In addition, enzymopathies were analyzed in the context of the sIEC metabolism. Computed results were compared with reported gastrointestinal (GI) pathologies and biochemical defects as well as with biomarker patterns used in their diagnosis. Based on our simulations, we propose that (i) sIEC metabolism is perturbed by numerous enzymopathies, which can be used to study cellular adaptive mechanisms specific for such disorders, and in the identification of novel co-morbidities, (ii) porphyrias are associated with both heme synthesis and degradation and (iii) disturbed intestinal gamma-aminobutyric acid synthesis may be linked to neurological manifestations of various enzymopathies. Taken together, the sIEC model represents a comprehensive, biochemically accurate platform for studying the function of sIEC and their role in whole body metabolism. [less ▲]

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See detailA community-driven global reconstruction of human metabolism.
Thiele, Ines UL; Swainston, N.; Fleming, Ronan MT UL et al

in Nature Biotechnology (2013), 31

Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus ‘metabolic reconstruction’, which ... [more ▼]

Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus ‘metabolic reconstruction’, which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ~2× more reactions and ~1.7× more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type–specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/. [less ▲]

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See detailSystems-level characterization of a host-microbe metabolic symbiosis in the mammalian gut.
Heinken, Almut Katrin UL; Sahoo, Swagatika UL; Fleming, Ronan MT UL et al

in Gut microbes (2013), 4(1), 28-40

The human gut microbiota consists of ten times more microorganisms than there are cells in our body, processes otherwise indigestible nutrients, and produces important energy precursors, essential amino ... [more ▼]

The human gut microbiota consists of ten times more microorganisms than there are cells in our body, processes otherwise indigestible nutrients, and produces important energy precursors, essential amino acids, and vitamins. In this study, we assembled and validated a genome-scale metabolic reconstruction of Bacteroides thetaiotaomicron (iAH991), a prominent representative of the human gut microbiota, consisting of 1488 reactions, 1152 metabolites, and 991 genes. To create a comprehensive metabolic model of host-microbe interactions, we integrated iAH991 with a previously published mouse metabolic reconstruction, which was extended for intestinal transport and absorption reactions. The two metabolic models were linked through a joint compartment, the lumen, allowing metabolite exchange and providing a route for simulating different dietary regimes. The resulting model consists of 7239 reactions, 5164 metabolites, and 2769 genes. We simultaneously modeled growth of mouse and B. thetaiotaomicron on five different diets varying in fat, carbohydrate, and protein content. The integrated model captured mutually beneficial cross-feeding as well as competitive interactions. Furthermore, we identified metabolites that were exchanged between the two organisms, which were compared with published metabolomics data. This analysis resulted for the first time in a comprehensive description of the co-metabolism between a host and its commensal microbe. We also demonstrate in silico that the presence of B. thetaiotaomicron could rescue the growth phenotype of the host with an otherwise lethal enzymopathy and vice versa. This systems approach represents a powerful tool for modeling metabolic interactions between a gut microbe and its host in health and disease. [less ▲]

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See detailA compendium of inborn errors of metabolism mapped onto the human metabolic network
Sahoo, Swagatika UL; Franzson; Jonsson, Jon J et al

in Molecular Biosystems (2012), 8(10), 2545-2558

Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through ... [more ▼]

Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases. [less ▲]

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