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•11-oxygenated androgen precursors are the preferred substrates for AKR1C3.•Oxidative 17βHSD enzymes regulate androgen activation.•Increased AKR1C3:17βHSD2 ratios favour the ...activation of 11-oxygenated androgens.•Computational modelling provides a valuable tool to study androgen metabolism.
The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 significantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α-androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.
Quantitative models of biochemical and cellular systems are used to answer a variety of questions in the biological sciences. The number of published quantitative models is growing steadily thanks to ...increasing interest in the use of models as well as the development of improved software systems and the availability of better, cheaper computer hardware. To maximise the benefits of this growing body of models, the field needs centralised model repositories that will encourage, facilitate and promote model dissemination and reuse. Ideally, the models stored in these repositories should be extensively tested and encoded in community-supported and standardised formats. In addition, the models and their components should be cross-referenced with other resources in order to allow their unambiguous identification.
BioModels Database http://www.ebi.ac.uk/biomodels/ is aimed at addressing exactly these needs. It is a freely-accessible online resource for storing, viewing, retrieving, and analysing published, peer-reviewed quantitative models of biochemical and cellular systems. The structure and behaviour of each simulation model distributed by BioModels Database are thoroughly checked; in addition, model elements are annotated with terms from controlled vocabularies as well as linked to relevant data resources. Models can be examined online or downloaded in various formats. Reaction network diagrams generated from the models are also available in several formats. BioModels Database also provides features such as online simulation and the extraction of components from large scale models into smaller submodels. Finally, the system provides a range of web services that external software systems can use to access up-to-date data from the database.
BioModels Database has become a recognised reference resource for systems biology. It is being used by the community in a variety of ways; for example, it is used to benchmark different simulation systems, and to study the clustering of models based upon their annotations. Model deposition to the database today is advised by several publishers of scientific journals. The models in BioModels Database are freely distributed and reusable; the underlying software infrastructure is also available from SourceForge https://sourceforge.net/projects/biomodels/ under the GNU General Public License.
The fidelity and reliability of disease model predictions depend on accurate and precise descriptions of processes and determination of parameters. Various models exist to describe within-host ...dynamics during malaria infection but there is a shortage of clinical data that can be used to quantitatively validate them and establish confidence in their predictions. In addition, model parameters often contain a degree of uncertainty and show variations between individuals, potentially undermining the reliability of model predictions. In this study models were reproduced and analysed by means of robustness, uncertainty, local sensitivity and local sensitivity robustness analysis to establish confidence in their predictions. Components of the immune system are responsible for the most uncertainty in model outputs, while disease associated variables showed the greatest sensitivity for these components. All models showed a comparable degree of robustness but displayed different ranges in their predictions. In these different ranges, sensitivities were well-preserved in three of the four models. Analyses of the effects of parameter variations in models can provide a comparative tool for the evaluation of model predictions. In addition, it can assist in uncovering model weak points and, in the case of disease models, be used to identify possible points for therapeutic intervention.
Glycolytic oscillations have been studied for well over 60 years, but aspects of their function, and mechanisms of regulation and synchronisation remain unclear. Glycolysis is amenable to mechanistic ...mathematical modelling, as its components have been well characterised, and the system can be studied at many organisational levels: in vitro reconstituted enzymes, cell free extracts, individual cells, and cell populations. In recent years, the emergence of individual cell analysis has opened new ways of studying this intriguing system.
Many organs have internal structures with spatially differentiated and sometimes temporally synchronized groups of cells. The mechanisms leading to such differentiation and coordination are not well ...understood. Here we design a diffusion-limited microfluidic system to mimic a multicellular organ structure with peripheral blood flow and test whether a group of individually oscillating yeast cells could form subpopulations of spatially differentiated and temporally synchronized cells. Upon substrate addition, the dynamic response at single-cell level shows glycolytic oscillations, leading to wave fronts traveling through the monolayered population and to synchronized communities at well-defined positions in the cell chamber. A detailed mechanistic model with the architectural structure of the flow chamber incorporated successfully predicts the spatial-temporal experimental data, and allows for a molecular understanding of the observed phenomena. The intricate interplay of intracellular biochemical reaction networks leading to the oscillations, combined with intercellular communication via metabolic intermediates and fluid dynamics of the reaction chamber, is responsible for the generation of the subpopulations of synchronized cells. This mechanism, as analyzed from the model simulations, is experimentally tested using different concentrations of cyanide stress solutions. The results are reproducible and stable, despite cellular heterogeneity, and the spontaneous community development is reminiscent of a zoned cell differentiation often observed in multicellular organs.
Upon infection by the malaria parasite Plasmodium falciparum, the glycolytic rate of a red blood cell increases up to 100-fold, possibly contributing to lactic acidosis and hypoglycemia in patients ...with severe malaria. This dramatic increase in glucose uptake and metabolism was correctly predicted by a newly constructed detailed enzyme kinetic model of glucose metabolism in the trophozoite-infected red blood cell. Subsequently, we expanded the model to simulate an infected red blood cell culture, including the different asexual blood-stage forms of the malaria parasite. The model simulations were in good agreement with experimental data, for which the measured parasitic volume was an important parameter. Upon further analysis of the model, we identified glucose transport as a drug target that would specifically affect infected red blood cells, which was confirmed experimentally with inhibitor titrations. This model can be a first step in constructing a whole-body model for glucose metabolism in malaria patients to evaluate the contribution of the parasite's metabolism to the disease state.
Most of the published quantitative models in biology are lost for the community because they are either not made available or they are insufficiently characterized to allow them to be reused. The ...lack of a standard description format, lack of stringent reviewing and authors' carelessness are the main causes for incomplete model descriptions. With today's increased interest in detailed biochemical models, it is necessary to define a minimum quality standard for the encoding of those models. We propose a set of rules for curating quantitative models of biological systems. These rules define procedures for encoding and annotating models represented in machine-readable form. We believe their application will enable users to (i) have confidence that curated models are an accurate reflection of their associated reference descriptions, (ii) search collections of curated models with precision, (iii) quickly identify the biological phenomena that a given curated model or model constituent represents and (iv) facilitate model reuse and composition into large subcellular models.
Motivation: In the Life Sciences, guidelines, checklists and ontologies describing what metadata is required for the interpretation and reuse of experimental data are emerging. Data producers, ...however, may have little experience in the use of such standards and require tools to support this form of data annotation.
Results: RightField is an open source application that provides a mechanism for embedding ontology annotation support for Life Science data in Excel spreadsheets. Individual cells, columns or rows can be restricted to particular ranges of allowed classes or instances from chosen ontologies. The RightField-enabled spreadsheet presents selected ontology terms to the users as a simple drop-down list, enabling scientists to consistently annotate their data. The result is 'semantic annotation by stealth', with an annotation process that is less error-prone, more efficient, and more consistent with community standards.
Availability and implementation: RightField is open source under a BSD license and freely available from http://www.rightfield.org.uk
Contact:
kwolstencroft@cs.man.ac.uk
The FAIRDOMHub is a repository for publishing FAIR (Findable, Accessible, Interoperable and Reusable) Data, Operating procedures and Models (https://fairdomhub.org/) for the Systems Biology ...community. It is a web-accessible repository for storing and sharing systems biology research assets. It enables researchers to organize, share and publish data, models and protocols, interlink them in the context of the systems biology investigations that produced them, and to interrogate them via API interfaces. By using the FAIRDOMHub, researchers can achieve more effective exchange with geographically distributed collaborators during projects, ensure results are sustained and preserved and generate reproducible publications that adhere to the FAIR guiding principles of data stewardship.
JWS Online is a repository of kinetic models, describing biological systems, which can be interactively run and interrogated over the Internet. It is implemented using a client–server strategy where ...the clients, in the form of web browser based Java applets, act as a graphical interface to the model servers, which perform the required numerical computations. Availability: The JWS Online website is publicly accessible at http://jjj.biochem.sun.ac.za/ with mirrors at http://www.jjj.bio.vu.nl/ and http://jjj.vbi.vt.edu/
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