Ek. Ainscow et Md. Brand, TOP-DOWN CONTROL ANALYSIS OF SYSTEMS WITH MORE THAN ONE COMMON INTERMEDIATE, European journal of biochemistry, 231(3), 1995, pp. 579-586
The analysis of the control of complex metabolic systems can be greatl
y simplified by application of the top-down approach of metabolic cont
rol analysis, in which the reactions of the system are grouped togethe
r into a small number of blocks connected by a common intermediate. Th
e experimental application of the top-down approach has so far been li
mited to systems that have only a single intermediate. In this study,
we demonstrate that the connectivity and summation theorems of metabol
ic control analysis hold with any number of intermediates between the
metabolic blocks, and in doing so show that top-down analysis is valid
for systems with multiple intermediates and so can be applied to most
metabolic systems regardless of their complexity; an example of such
an application is provided. Top-down control analysis has successfully
described the control of mitochondrial respiration by dividing the sy
stem into three blocks, the respiratory chain, phosphorylation system
and proton leak, all linked by a single intermediate, proton motive fo
rce. Here, we subdivide the respiratory chain into succinate consumers
and cytochrome oxidase so that a second intermediate, cytochrome c re
dox state, is generated. Despite the fact that the redox state of cyto
chrome c is not measured, we solve the control over the system fluxes.
In common with previous studies, we find that under conditions where
there is no ATP turnover (state 4), respiration is largely controlled
by proton leak, while at maximal ATP turnover (state 3) respiration is
controlled by the respiratory chain and the phosphorylating system. I
n state 4, 85% of the control by the respiratory chain resides with cy
tochrome oxidase. As ATP turnover increases, the respiration rate incr
eases, and the control by the respiratory chain shifts from cytochrome
oxidase to the succinate consumers, so that in state 3 83% of the con
trol by the respiratory chain lies in the reactions between succinate
and cytochrome c and only 17% resides with cytochrome oxidase.