Metabolic control analysis to identify optimal drug targets.
This chapter describes the basic principles of Metabolic Control Analysis (MCA) which is a quantitative methodology to evaluate the importance and relative contribution of individual metabolic steps in the overall functioning of a particular system. The control on the flux through a metabolic pathway or subsystem can be quantified by the control coefficients of the individual enzymes or components which reflects the extent to which the component is rate-limiting. The perturbation of an individual step is measured by its elasticity coefficient. The effect of perturbation of a single step on the entire pathway or subsystem is, in turn, measured by the response coefficient. Differential control analysis can be used to compare flux through a single metabolic pathway in a pathogen with the same pathway in its host to identify uniquely vulnerable steps with the greatest potential for specifically inhibiting flux through the pathogen metabolic pathway. The utility of this methodology is illustrated with the glycolysis in Trypanosomes and with oncogenic signaling.
Hornberg
Jorrit J
JJ
Department of Molecular Cell Physiology, Institute for Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands. jorrit.hornberg@organon.com
Bruggeman
Frank J
FJ
Bakker
Barbara M
BM
Westerhoff
Hans V
HV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008660:Metabolism / Q000187:drug effects*; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents