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Metabolic control analysis in drug discovery and disease

Nature Biotechnology volume 20, pages 243–249 (2002)Cite this article

Abstract

Metabolic control analysis (MCA) provides a quantitative description of substrate flux in response to changes in system parameters of complex enzyme systems. Medical applications of the approach include the following: understanding the threshold effect in the manifestation of metabolic diseases; investigating the gene dose effect of aneuploidy in inducing phenotypic transformation in cancer; correlating the contributions of individual genes and phenotypic characteristics in metabolic disease (e.g., diabetes); identifying candidate enzymes in pathways suitable as targets for cancer therapy; and elucidating the function of "silent" genes by identifying metabolic features shared with genes of known pathways. MCA complements current studies of genomics and proteomics, providing a link between biochemistry and functional genomics that relates the expression of genes and gene products to cellular biochemical and physiological events. Thus, it is an important tool for the study of genotype–phenotype correlations. It allows genes to be ranked according to their importance in controlling and regulating cellular metabolic networks. We can expect that MCA will have an increasing impact on the choice of targets for intervention in drug discovery.

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Figure 1: Definition of a control coefficient of an enzymatic step.
Figure 2: A double logarithmic plot of the dependence of tumor cell proliferation, versus an hypothetical enzyme A activity.

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Acknowledgements

This work was supported by grants from the Spanish Government Science Technology Ministry (PPQ2000-0688-C05-04) and Health Ministry (FISS 00-1120), the European Commission Grant INCO-COPERNICUS (ERBIC15CT960307), and the NATO Science Program (SA, LST.CLG.976283). The Biomedical Mass Spectrometry Facility is supported by USPHS grants P01-CA42710 to the UCLA Clinical Nutrition Research Unit, Stable Isotope Core, and M01-RR00425 to the General Clinical Research Center.

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  1. Department of Biochemistry and Molecular Biology, CeRQT–Parc Científic de Barcelona (PCB), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Marti i Franques 1, Barcelona, 08028, Catalonia, Spain

    Marta Cascante, Begoña Comin-Anduix, Pedro de Atauri & Josep J. Centelles

  2. UCLA School of Medicine, Harbor-UCLA Research and Education Institute, Torrance, 90502, CA, USA

    Laszlo G. Boros & Paul W.-N. Lee

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  1. Marta Cascante
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Correspondence to Marta Cascante.

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Cascante, M., Boros, L., Comin-Anduix, B. et al. Metabolic control analysis in drug discovery and disease. Nat Biotechnol 20, 243–249 (2002). https://doi.org/10.1038/nbt0302-243

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