From owner-metabolic-reg@net.bio.net Thu Oct 12 23:00:00 1995 Path: biosci!daresbury!not-for-mail From: daf@bms.brookes.ac.uk (David Fell) Newsgroups: bionet.metabolic-reg Subject: Metabolic control paper Date: 13 Oct 1995 13:25:39 +0100 Lines: 71 Sender: lpddist@mserv1.dl.ac.uk Distribution: bionet Message-ID: <45lls3$bvo@mserv1.dl.ac.uk> X-Sender: daf@darwin content-length: 3060 Original-To: btk-mca@dl.ac.uk Pedro Mendes is quite right that the problem is we have not been keeping enough science going on this news group. So here's a contribution, the abstract and introduction of our latest paper: Physiological Control of Metabolic Flux: the Requirement for Multisite Modulation by David A. Fell Simon Thomas Biochem. J. 311, 35-39, 1995 Synopsis Biochemists have long assumed that the flux through a metabolic pathway can be controlled by the activity of a key regulatory enzyme near the beginning of the pathway. We present the accumulating evidence that every step in this assumption is flawed. Instead, effective physiological control of metabolism is shown to involve simultaneous multisite modulation through action on a number of enzymes. Introduction Since Blackman proposed the concept of the `rate--limiting step' in 1905, it has dominated the approach to understanding the control of metabolic pathways. For example, it was endorsed in Krebs' concept of `pacemaker' enzymes , which he saw as the target sites for hormone and drug action on metabolism. Even though the theory of Metabolic Control Analysis has since shown that control can be distributed over many steps in a pathway, and that the degree of control of any given step can be quantified by its flux control coefficient, qualitative explanations of how a pathway can be controlled have not been greatly affected. Indeed, although Metabolic Control Analysis has been increasingly adopted in metabolic biochemistry, and experiments have confirmed both that control is generally distributed and that genuinely rate--limiting enzymes are rare, it has also legitimized the concept that an enzyme that responds to some external controlling factor can be an agent of metabolic control provided the enzyme has a finite flux control coefficient. However, we shall cite arguments that such mechanisms cannot be responsible for large changes in metabolic flux. On the other hand, recent theoretical developments arising from Metabolic Control Analysis do allow us to characterize how large changes in metabolic flux could be implemented; they can only be achieved with minimal disturbance of metabolite concentrations and fluxes in other pathways by coordinated changes in the activities of many of the enzymes in the pathway, and this can be shown to be a common mechanism of control. Related experimental and theoretical evidence also contradicts the view that regulatory enzymes exhibiting allosteric properties are effective agents for control of metabolic flux. Our conclusion is that their more significant role is in homeostasis. In consequence, different approaches are needed both to the study and explanation of metabolic control. Comments invited. Reprints still awaited from the publishers. ========================================================= David Fell, School of Biological & Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP, Tel. +44 (0)1865 483247 UK FAX +44 (0)1865 484017 daf@bms.brookes.ac.uk .