BioSystems 55 2000 73 – 81
Cellular information transfer regarded from a stoichiometry and control analysis perspective
Stefan Schuster
a,
, Boris N. Kholodenko
b
, Hans V. Westerhoff
c,d
a
Department of Bioinformatics, Max Delbru¨ck Center for Molecular Medicine, D-
13092
Berlin-Buch, Germany
b
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson Uni6ersity, Philadelphia PA
19107
-
6799
, USA
c
Department of Molecular Cell Physiology, Vrije Uni6ersiteit Amsterdam, De Boelelaan
1087
, NL-
1081
HV, Amsterdam, The Netherlands
d
E.C. Slater Institute, Uni6ersity of Amsterdam, Plantage Muidergracht
12
, NL-
1018
TV Amsterdam, The Netherlands
Abstract
Metabolic control analysis MCA allows one to formalize important aspects of information processing in living cells. For example, information processing via multi-level enzyme cascades can be quantified in terms of the response
coefficient of a cellular target to a signal. In many situations, control and response coefficients cannot be determined exactly for all enzymes involved, owing to difficulties in ‘observing’ all enzymes experimentally. Here, we review a
number of qualitative approaches that were developed to cope with such situations. The usefulness of the concept of null-space of the stoichiometry matrix for analysing the structure of intracellular signaling networks is discussed. It
is shown that signal transduction operates very efficiently when the network structure is such that the null-space matrix can be block-diagonalized which may or may not imply that the network consists of several disconnected
parts and some enzymes have low elasticities to their substrates. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Enzyme cascades; Fructose-2,6-bisphosphate cycle; Metabolic control analysis; Response coefficients; Signal transduction; Stoichiometric analysis
www.elsevier.comlocatebiosystems
1. Introduction
The storage and processing of information is a striking feature of living organisms. To describe
and analyze this feature is one of the major challenges in modern biology. Although powerful
theoretical tools for this purpose such as Shan- non’s information theory exist, the specific prop-
erties of biological systems such as their network structure and hierarchic and spatial organization
cannot completely be covered by these tools so far Bray, 1995; Fisher et al., 1999. A multitude of
intracellular and intercellular signaling pathways and networks have been identified. Part of these
pathways is made up of enzyme cascades such as the glutamine synthetase cascade Jaggi et al.,
1997 and the glycogen-phosphorylaseglycogen-
Corresponding author. Tel.: + 49-30-94063125; fax: + 49- 30-94062834.
E-mail address
:
schusterbp.biologie.hu-berlin.de S. Schus- ter
0303-264700 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 3 - 2 6 4 7 9 9 0 0 0 8 5 - 4
synthase system Chock et al., 1980. In recent years,
the mitogen-activated
protein kinase
MAPK signaling pathway has been intensely investigated Hsueh and Law, 1999; Bornfeldt and
Krebs, 1999. The interconnection of several path- ways has also been studied Bray, 1995. Al-
though these structures have a number of similarities with metabolic pathways and net-
works, there is an essential difference in that there is no or only a very small mass flow between the
components of a signaling network.
In living cells, information is frequently pro- cessed in hierarchic systems. In gene expression,
for example, we can discern the levels of DNA, mRNA, and proteins. Between the levels of such
hierarchies, there is flow of information, but again usually no mass flow. In the present paper, we
shall analyze what topological and kinetic proper- ties a system should have so that information can
be transmitted efficiently without or with only a small concomitant mass flow.
The understanding of the regulatory properties of biochemical systems has been greatly improved
by Metabolic Control Analysis MCA. This is a theoretical framework through which the effect of
changes in enzyme activity on the fluxes, concen- trations and other relevant variables characteriz-
ing biochemical systems at steady state can be determined for review see Westerhoff et al., 1995;
Heinrich and Schuster, 1996; Fell, 1997. The largest part of the theory so far developed in
MCA, concerns systems in which the substances are connected by mass flow e.g. Westerhoff and
Van Dam, 1987; Reder, 1988; Brown et al., 1990; Kholodenko et al., 1998; Schuster and Wester-
hoff, 1999. However, also enzyme cascades and other hierarchic systems that are capable of signal
transfer have been analyzed Small and Fell, 1990; Kahn and Westerhoff, 1991; Kholodenko et al.,
1997. In the present paper, we will elaborate on the question as to whether information flow can
be dealt with by MCA. Moreover, we will study the specific topological properties of cellular sig-
naling systems. Special attention will be paid to the fact that knowledge of kinetic parameters of
all the enzymes involved in the network is often incomplete.
2. Metabolic control analysis in the case of imperfect knowledge of kinetic parameters
