I had two insights (srere, 1965) into the nature of metabolic regulation before I heard of Kacser & Burns (1973) or Heinrich & Rapoport (1974). I was struck at that time by the large number of metabolites that affected the rate of a number of individual enzymes such as the glycolytic enzyme, phosphofructokinase, and the fatty acid biosynthetic enzyme, acetyl-CoA carboxylase. I noticed also for each of the enzymes of a single pathway, there existed a control mechanism by a metabolite which one could consider rate-regulating. In spite of this, the theory of metabolic regulation by single rate-limiting steps was adhered to then and to a certain extent even now. Other inconsistencies in the "rate-limiting step-allosteric enzyme" hypotheses became apparent. Thus, in the Krebs tricarboxylate cycle the allosteric enzyme, isocitrate dehydrogenase (NAD~+), did not occur at the "beginning" or at the first step in an unbranched pathway. I learned also that computers needed a large number of redundant circuits to improve reliability and that stable circuits could be constructed from randomly responding elements (McCulloch & Pitts, 1943). Thus, I felt that simplistic ideas about rate-limiting steps in metabolism were not realistic and that complexity and redundancy themselves could result in stability in complex reaction organizations and their regulation.
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