Tracing regulatory routes in metabolism using generalised supply-demand analysis

Abstract

BackgroundGeneralised 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.ResultsMultiple 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.ConclusionsIndirect 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0236-1) contains supplementary material, which is available to authorized users.

Balancing energy supply during photosynthesis – a theoretical perspective

“…This energy is used to drive the carbon dioxide reduction and fixation processes known as the ‘dark reactions’. Thus, the photosynthetic light and dark reactions can be viewed as a molecular economy supply–demand system (Hofmeyr and Cornish‐Bowden , Rohwer and Hofmeyr , Christensen et al ).…”

Control and regulation of pathways via negative feedback

“…The numerators in the flux control equations therefore indicate the routes taken by a disturbance [60,61].…”

Delving deeper: Relating the behaviour of a metabolic system to the properties of its components using symbolic metabolic control analysis

“…As mentioned, results obtained during a previous study of a model of pyruvate branch 188 metabolism in Lactococcus lactis [29] were revisited in this paper. This model was 189 originally constructed by Hoefnagel et al [21], and was obtained from the JWS online 190 model database [45] in the PySCeS model descriptor language (see 191 http://pysces.sourceforge.net/docs/userguide.html).…”

“…Previous work in this regard has pointed to 57 redox balance as playing an important role [24][25][26][27][28]. As part of a larger study that 58 focussed on the quantification of regulatory routes in metabolic models [29], we utilised 59 generalised supply-demand analysis [30] to uncover the effect of the redox balance on 60 the different metabolic branches of pyruvate metabolism of Lactococcus lactis using a 61 previously published metabolic model [21]. In that study, an increase in NADH/NAD + 62 was shown to decrease flux towards acetaldehyde and ethanol, mirroring past 63 experimental [24][25][26][27] and FBA modelling [28] findings.…”

“…The value of φ N was varied directly rather than modulating its demand (the activity 200 of NADH oxidase) for two reasons. First, we wanted to mirror the methodology used in 201 our original study [29], so that we could further explore the results obtained there.…”