Tài liệu Báo cáo khoa học: Steady-state kinetic behaviour of functioning-dependent structures docx

Steady-state kinetic behaviour of functioning-dependent

structures

Michel Thellier1,3, Guillaume Legent1

, Patrick Amar2,3, Vic Norris1,3 and Camille Ripoll1,3

1 Laboratoire ‘Assemblages mole´ culaires: mode´lisation et imagerie SIMS’, Faculte´ des Sciences de l’Universite´ de Rouen,

Mont-Saint-Aignan Cedex, France

2 Laboratoire de recherche en informatique, Universite´ de Paris Sud, Orsay Cedex, France

3 Epigenomics Project, Genopole, Evry, France

Numerous studies have shown that proteins involved

in metabolic or signalling pathways are often distri￾buted nonrandomly, as multimolecular assemblies

[1–15]. Such assemblies range from quasi-static, multi￾enzyme complexes (such as the fatty acid synthase or

the a-oxo acid dehydrogenase systems [5]) to transient,

dynamic protein associations [2,3,7,15,16]. Comparison

of yeast and human multiprotein complexes has shown

that conservation across species extends from single

proteins to protein assemblies [11]. Multi-molecular

assemblies may comprise proteins but also nucleic

acids, lipids, small molecules and inorganic ions. Such

assemblies may interact with membranes, skeletal ele￾ments and ⁄ or cell organelles [3,4,15,17]. They have

been termed metabolons, transducons and repairo￾somes in the case of metabolic pathways [3,10,18–23],

signal transduction [24] and DNA repair [12], respect￾ively, or, more generally, hyperstructures [17,25–28].

According to Srere [3], metabolons are enzyme

assemblies in which intermediates are channelled from

each enzyme to the next without diffusion of these

intermediates into the surrounding cytoplasm [2–

7,9,15,23,29–33]. Potential advantages of channelling

[7,9,15,30,31,34,35] are (i) reduction in the size of the

pools of intermediates (a point, however, contested by

some authors [36,37]), (ii) protection of unstable or

scarce intermediates by maintaining them in a protein￾bound state, (iii) avoidance of an ‘underground’ meta￾bolism in which intermediates become the substrates of

other enzymes [38], and (iv) protection of the cytoplasm

from toxic or very reactive intermediates. The terms sta￾tic and dynamic channelling have been used to describe,

respectively, the channelling in a quasipermanent me￾tabolon and in a transient association between two

enzymes occurring while the intermediate metabolite is

transferred from the first enzyme to the second [39,40].

Keywords

enzyme kinetics; metabolic or signalling

pathways; mathematical modelling; protein

associations

Correspondence

M. Thellier, Laboratoire Assemblages

mole´ culaires: mode´lisation et imagerie SIMS

FRE CNRS 2829, Faculte´ des Sciences de

l’Universite´ de Rouen, F-76821 Mont-Saint￾Aignan Cedex, France

Fax: +33 2 35 14 70 20

Tel: +33 2 35 14 66 82

E-mail: [email protected]

(Received 12 January 2006, revised 26 June

2006, accepted 20 July 2006)

doi:10.1111/j.1742-4658.2006.05425.x

A fundamental problem in biochemistry is that of the nature of the

coordination between and within metabolic and signalling pathways. It is

conceivable that this coordination might be assured by what we term func￾tioning-dependent structures (FDSs), namely those assemblies of proteins

that associate with one another when performing tasks and that disassoci￾ate when no longer performing them. To investigate a role in coordination

for FDSs, we have studied numerically the steady-state kinetics of a model

system of two sequential monomeric enzymes, E1 and E2. Our calculations

show that such FDSs can display kinetic properties that the individual

enzymes cannot. These include the full range of basic input⁄ output charac￾teristics found in electronic circuits such as linearity, invariance, pulsing

and switching. Hence, FDSs can generate kinetics that might regulate and

coordinate metabolism and signalling. Finally, we suggest that the occur￾rence of terms representative of the assembly and disassembly of FDSs in

the classical expression of the density of entropy production are character￾istic of living systems.

Abbreviation

FDS, functioning-dependent structure.

FEBS Journal 273 (2006) 4287–4299 ª 2006 The Authors Journal compilation ª 2006 FEBS 4287