Tài liệu Báo cáo khoa học: Catabolite repression in Escherichia coli – a comparison of modelling

Catabolite repression in Escherichia coli – a comparison of

modelling approaches

Andreas Kremling, Sophia Kremling and Katja Bettenbrock

Systems Biology Group, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany

Research in systems biology requires experimental

effort as well as theoretical attempts to elucidate the

general principles of cellular dynamics and control

and to help to improve molecular processes for engi￾neering purposes or drug design. This interdisciplinary

approach provides a promising method for advances

in biotechnology and molecular medicine. In systems

biology, quantitative experimental data and mathe￾matical models are combined in an attempt to obtain

information on the dynamics and regulatory structures

of the systems. However, depending on the degree of

biological knowledge and the amount of quantitative

data, the models developed so far differ in their degree

of granularity, starting with a simple on ⁄ off binary

description of the state variables of the system and

ending with fully mechanistic models. Carbohydrate

uptake via the phosphoenolpyruvate-dependent phos￾photransferase system (PTS) in Escherichia coli is one

of the best studied biochemical networks from theo￾retical and experimental points of view, and has

Keywords

Escherichia coli; model verification; modular

modelling; phosphotransferase system; time

hierarchies

Correspondence

A. Kremling, Systems Biology Group, Max

Planck Institute for Dynamics of Complex

Technical Systems, Sandtorstr. 1, 39106

Magdeburg, Germany

Fax: +49 0391 6110 526

Tel: +49 0391 6110 466

E-mail: [email protected]

(Received 26 September 2008, revised 14

November 2008, accepted 19 November

2008)

doi:10.1111/j.1742-4658.2008.06810.x

The phosphotransferase system in Escherichia coli is a transport and sen￾sory system and, in this function, is one of the key players of catabolite

repression. Mathematical modelling of signal transduction and gene expres￾sion of the enzymes involved in the transport of carbohydrates is a promis￾ing approach in biotechnology, as it offers the possibility to achieve higher

production rates of desired components. In this article, the relevance of

methods and approaches concerning mathematical modelling in systems

biology is discussed by assessing and comparing two comprehensive mathe￾matical models that describe catabolite repression. The focus is thereby on

modular modelling with the relevant input in the central modules, the

impact of quantitative model validation, the identification of control struc￾tures and the comparison of model predictions with respect to the available

experimental data.

Abbreviations

cAMP, cyclic AMP (signalling molecule); Crp, catabolite repression protein (transcription factor); CyaA, adenylate cyclase (protein,

synthesizes cAMP); dFBA, dynamic FBA (takes into account the slow dynamics of extracellular components); EI, enzyme I (protein,

component of the PTS); EIIA, enzyme IIA (protein, component of the PTS, ‘output’ of the system as it activates the synthesis of cAMP);

EIIBC (PtsG), enzyme IIBC (main membrane standing transport protein for glucose uptake); FBA, flux balance analysis (tool to determine the

flux distribution in cellular networks, requires steady-state conditions); HPr, histidine-containing protein (component of the PTS); LacZ,

protein of the lactose degradation pathway (b-galactodidase); Mlc, repressor protein (inhibits the synthesis of EIIBC if glucose is not present

in the medium); o.d.e., ordinary differential equation (basic structure of a mathematical model, it describes the temporal changes of a

component in the network, must be solved numerically); PTS, phosphotransferase system (uptake and sensory system in many bacteria,

consists of several proteins); rFBA, regulatory FBA (takes into account the transcriptional regulatory network to describe the presence or

absence of the enzyme of the network as a function of the environmental conditions).

594 FEBS Journal 276 (2009) 594–602 ª 2008 The Authors Journal compilation ª 2008 FEBS