Technological and Medical Implications of Metabolic Control Analysis

Two decades have passed since the mechanisms of protein synthesis became well enough understood to permit the genetic modification oforganisms. An impressive amount of new knowledge has emerged from the new technology, but much ofthe promise of20years ago has notyet been fulfilled. In biotechnology, efforts to increase the yields of commercially valuable metabolites have been less successful than ex pected, and when they have succeeded it has often been as much from selective breeding as from new methods. The cell is more complicated than what is presented in the classical teaching of biochemistry, it contains more structure than was dreamed of 20 years ago, and the behaviour ofany systemofenzymes is more elaborate than can be explained in terms ofa single supposedly rate-limiting enzyme. Even if classical enzymology and meta bolism may have seemed rather unfashionable during the rise ofmolecular biology, they remain central to any modification ofthe metabolic behaviour oforganisms. As such modification is essential in much ofbiotechnology and drug development, bio technologists can only ignore these topics at their peril.

Zusammenfassung
Proceedings of the NATO Advanced Research Workshop, Visegrad, Hungary, 10-16 April 1999

Inhalt

1. Provoking an Argument: Problems with Current Approaches to the Analysis of Biochemical Systems.- 1. Snapshots of systems: metabolic control analysis and biotechnology in the post-genomic era.- 2. Moiety conservation and flux enhancement.- 3. On the universality of the universal method.- 2. Imposing Discipline: Manipulation of Organisms for Technological Ends.- 4. Life is complicated.- 5. Regulation and redirection of metabolism: incorporating regulatory information influx calculation.- 6. Recent developments in metabolic pathway analysis and their potential implications for biotechnology and medicine.- 7. Quantifying the importance of regulatory loops in homeostatic control mechanisms: hierarchical control of DNA supercoiling.- 8. An integrated approach to theanalysis of the control andregulation of cellular systems.- 3. Understanding Health and Disease: Why Organisms Behave as They Do.- 9. Mechanism of carcinogenesis by polycyclic aromatic hydrocarbons: aneuploidy precedes malignant transformation and occurs in all cancers.- 10. Metabolic control analysis shows how aneuploidy causes cancer.- 11. The control strength of glucokinase in hepatocytes: a predictor of metabolic defects in maturity onset diabetes of the young, type 2.- 12. Metabolic distress associated with impaired control by alternative substrates: two examples taken from purine metabolism.- 13. Regulation of ATP supply in muscle: implications for importance of flux control coefficients and for the genesis of mitochondrial myopathies.- 14. Regulation of energy metabolism in hepatocytes.- 15. Combined NMR experimental and computer-simulation study of 2,3-bisphosphoglycerate metabolism in human erythrocytes.- 4. Taking Aim: Use of Metabolic Models to Identify Drug Targets.- 16. Computational approaches to the study of biochemical pathways and metabolic control.- 17. Using metabolic control analysis to improve the selectivity and effectiveness of drugs against parasitic diseases.- 18. Computer simulation as a tool for studying metabolism and drug design.- 19. Use of metabolic control analysis to design a new strategy for cancer therapy.- 5. Facing Reality: Not Just a Bag of Enzymes.- 20. Implications of cytoarchitectural analysis.- 21. Probing the cell interior with NMR spectroscopy.- 22. Metabolite channelling and protein-protein interactions in the urea synthesis pathway.- 23. Intracellular distribution of glycogen synthase: Another regulatory mechanism of glycogen metabolism?.- 24. Supramolecular organization and substrate channelling in the mammalian translation system.- 25. Analysis of co-localization of glycolytic enzymes in flight muscle and its relation to muscle function in Drosophila.- 6. Thinking About Metabolism: The Relationship Between Control and Regulation.- 26. Metabolic control from the back benches: biochemistry towards biocomplexity.- 27. Physiological consequences of a non-regulated mutant phosphofructokinase in Escherichia coli.- 28. Time-dependent or steady-state control of metabolic systems?.- 29. Multisite modulation in the control of glycolysis: balance of supply and demand?.- 30. Exercising control when control is distributed.- 31. Metabolic control design: implications and applications.- 32. Determining elasticities in situ.- 33. Coordination and homeostasis in the response to multiple signals: role of metabolic cascades.- 34. Putting the cart before the horse: designing a metabolic system in order to understand it.- 35. Predicting the structural design of metabolic pathways: an evolutionary approach.- 36. Glycogen structure: an evolutionary view.- 7. Taking Stock: Control Analysis in the Context of Metabolic Regulation.- 37. From control to regulation: a new prospect for metabolic control analysis.- 38. Metabolic control and metabolons in the millennium.- In memoriam: Paul Srere, 1925-1999.- A. Cornish-Bowden.- Contributors.