Integrating metabolic pathway fluxes with gene-to-enzyme expression rates

The concept of symmorphosis emphasizes that sequential steps in physiological systems are structurally and functionally matched to each other and to in vivo maximum loads. Examination of metabolic pathways, specifically 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 sustained with minimal changes in concentrations of pathway intermediates. This is true for both low and high capacity pathways and is consistent with the ‘economic design’ expectations of symmorphosis. (ii) In the glycolytic pathway, some enzymes (termed hE) occur at high concentrations and high activities, while others (lE), usually enzymes operating in vivo far from equilibrium, occur at lower concentrations and lower activities. Although genes for glycolytic enzymes are thought to be coordinately regulated by being linked to common inducing or repressing signals, during long term (phylogenetic) up or down regulation of glycolytic capacity, the expression of genes for hE type enzymes are adjusted the most; the expression of lE type (usually enzymes functioning far from equilibrium) are up or down regulated the least. These differences are of lower magnitude but are also evident in short term up or down regulation of the pathway of glycolysis (such as induction by hypoxia and repression during electrical stimulation and fiber type transformation in muscle). (iii) When considered together, these data require that, despite coordinate regulation of the overall functional unit (glycolysis), the expression pathway for each enzyme in the sequence must be under unique feedback regulation, implying an unique information flow circuit (gene→enzyme→gene) for each enzyme in the metabolic pathway. (iv) The matching of flux capacities in linked sequences 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 with 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 within a single pathway self modulate or fine tune their own expression rate according to their functional role in the pathway remains unanswered, although a number of potential regulatory mechanisms are known.