Oxygen, homeostasis, and metabolic regulation.

Even a cursory review of the literature today indicates that two views dominate experimental approaches to metabolic regulation. Model I assumes that cell behavior is quite similar to that expected for a bag of enzymes. Model II assumes that 3-D order and structure constrain metabolite behavior and that metabolic regulation theory has to incorporate structure to ever come close to describing reality. The phosphagen system may be used to illustrate that both approaches lead to very productive experimentation and significant advances are being made within both theoretical frameworks. However, communication between the two approaches or the two 'groups' is essentially nonexistent and in many cases (our own for example) some experiments are done in one framework and some in the other (implying some potential schizophrenia in the field). In our view, the primary paradox and problem which no one has solved so far is that essentially all metabolite concentrations are remarkably stable (are homeostatic) over large changes in pathway fluxes. For muscle cells O2 is one of the most perfectly homeostatic of all even though O2 delivery and metabolic rate usually correlate in a 1:1 fashion. Four explanations for this behavior are given by traditional metabolic regulation models. Additionally, there is some evidence for universal O2 sensors which could help to get us out of the paradox. In contrast, proponents of an ultrastructurally dominated view of the cell assume intracellular perfusion or convection as the main means for accelerating enzyme-substrate encounter and as a way to account for the data which have been most perplexing so far: the striking lack of correlation between changes in pathway reaction rates and changes in concentrations of pathway substrates and intermediates, including oxygen. The polarization illustrated by these two views of living cells extends throughout the metabolic regulation field (and has caused the field to progress along two surprisingly independent paths with minimal communication between them). The time may have come when cross talk between the two fields may be useful.