Tracing regulatory routes in metabolism using generalised supply-demand analysis
Date
2015-12
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: Generalised supply-demand analysis is a conceptual framework that views metabolism as a
molecular economy. Metabolic pathways are partitioned into so-called supply and demand blocks that produce and consume a particular intermediate metabolite. By studying the response of these reaction blocks to perturbations in the concentration of the linking metabolite, different regulatory routes of
interaction between the metabolite and its supply and demand blocks can be identified and their
contribution quantified. These responses are mediated not only through direct substrate/product
interactions, but also through allosteric effects. Here we subject previously published kinetic
models of pyruvate metabolism in Lactococcus lactis and aspartate-derived amino acid synthesis in
Arabidopsis thaliana to generalised supply-demand analysis.
Results: Multiple routes of regulation are brought about by different mechanisms in each model,
leading to behavioural and regulatory patterns that are generally difficult to predict from simple
inspection of the reaction networks depicting the models. In the pyruvate model the moiety-conserved cycles of ATP/ADP and NADH/NAD+ allow otherwise independent metabolic branches to communicate. This causes the flux of one ATP-producing reaction block to increase in response to an increasing ATP/ADP ratio, while an NADH-consuming block flux decreases in response to an increasing NADH/NAD+ ratio for certain ratio value ranges. In the aspartate model, aspartate semialdehyde can inhibit its supply block directly or by
increasing the concentration of two amino acids (Lys and Thr) that occur as intermediates in demand
blocks and act as allosteric inhibitors of isoenzymes in the supply block. These different routes
of interaction from aspartate semialdehyde are each seen to contribute differently to the
regulation of the aspartate semialdehyde supply block.
Conclusions: Indirect routes of regulation between a metabolic intermediate and a reaction block
that either produces or consumes this intermediate can play a much larger regulatory role than
routes mediated through direct interactions. These indirect routes of regulation can also result in
counter-intuitive metabolic behaviour. Performing generalised supply-demand analysis on two
previously published models demonstrated the utility of this method as an entry point in the
analysis of metabolic behaviour and the potential for obtaining novel results from previously
analysed models by using new approaches.
Description
CITATION: Christensen, C. D., Hofmeyr, J. H. S. & Rohwer, J. M. 2015. Tracing regulatory routes in metabolism using generalised supply-demand analysis. BMC Systems Biology, 9(1): 89, doi: 10.1186/s12918-015-0236-1.
Publication of this article was funded by the Stellenbosch University Open Access Fund.
The original publication is available at http://bmcmusculoskeletdisord.biomedcentral.com
Publication of this article was funded by the Stellenbosch University Open Access Fund.
The original publication is available at http://bmcmusculoskeletdisord.biomedcentral.com
Keywords
Generalised supply-demand analysis, Metabolic control -- Analysis, Metabolism -- Mathematical models, Arabidopsis thaliana, Lactococcus lactis, Metabolism -- Regulation, Metabolites -- Analysis, Biotransformation (Metabolism), Allosteric regulation
Citation
Christensen, C. D., Hofmeyr, J. H. S. & Rohwer, J. M. 2015. Tracing regulatory routes in metabolism using generalised supply-demand analysis. BMC Systems Biology, 9(1): 89, doi: 10.1186/s12918-015-0236-1