INTEGRATING METABOLIC PATHWAY FLUXES WITH GENE-TO-ENZYME EXPRESSION RATES

The concept of symmorphosis emphasizes that sequential steps in physio logical systems are structurally and functionally matched to each othe r and to in vivo maximum loads. Examination of metabolic pathways, spe cifically glycolysis, in this framework led to several conclusions. (i ) Linked enzyme catalyzed reaction sequences are so closely integrated with each other that large changes in flux through the pathway are su stained with minimal changes in concentrations of pathway intermediate s. This is true for both low and high capacity pathways and is consist ent with the 'economic design' expectations of symmorphosis. (ii) In t he glycolytic pathway, some enzymes (termed hE) occur at high concentr ations and high activities, while others (IE), usually enzymes operati ng in vivo far from equilibrium, occur at lower concentrations and low er activities. Although genes for glycolytic enzymes are thought to be coordinately regulated by being linked to common inducing or repressi ng signals, during long term (phylogenetic) up or down regulation of g lycolytic capacity, the expression of genes for hE type enzymes are ad justed the most; the expression of IE type (usually enzymes functionin g far from equilibrium) are up or down regulated the least. These diff erences are of lower magnitude but are also evident in short term up o r down regulation of the pathway of glycolysis (such as induction by h ypoxia and repression during electrical stimulation and fiber type tra nsformation in muscle). (iii) when considered together, these data req uire that, despite coordinate regulation of the overall functional uni t (glycolysis), the expression pathway for each enzyme in the sequence must be under unique feedback regulation, implying an unique informat ion flow circuit (gene --> enzyme --> gene) for each enzyme in the met abolic pathway. (iv) The matching of flux capacities in linked sequenc es thus seems to apply 'across the board' - not only horizontally but also vertically - in cell metabolic design. That is, up or down change in demand for glycolytic function(horizontal pathway) is integrated w ith up or down regulation of gene expression (vertical pathway). While a general feedback loop from metabolism to genes has been previously recognized, the step-by-step specificity required for-the pathway as a whole has been overlooked. The intriguing question of how enzymes wit hin a single pathway self modulate or fine tune their own expression r ate according to their functional role in the pathway remains unanswer ed, although a number of potential regulatory mechanisms are known. (C ) 1998 Elsevier Science Inc. All rights reserved.