Hochachka P W
Dept. of Zoology, University of British Columbia, Vancouver, Canada.
Adv Exp Med Biol. 2000;475:311-35. doi: 10.1007/0-306-46825-5_30.
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.
即便只是粗略地回顾一下当今的文献，也会发现有两种观点主导着代谢调节的实验方法。模型I假定细胞行为与一袋酶的预期行为非常相似。模型II假定三维秩序和结构会限制代谢物的行为，并且代谢调节理论必须纳入结构因素，才能接近描述现实。磷酸原系统可用于说明这两种方法都能带来非常有成效的实验，并且在这两个理论框架内都取得了重大进展。然而，这两种方法或两个“阵营”之间基本上不存在交流，而且在许多情况下（例如我们自己的研究），一些实验是在一个框架内进行的，而另一些则是在另一个框架内进行的（这意味着该领域存在一些潜在的不一致性）。在我们看来，迄今为止还没有人解决的主要矛盾和问题是，在途径通量发生大幅变化时，基本上所有代谢物浓度都非常稳定（处于稳态）。对于肌肉细胞来说，氧气是所有物质中最完美的稳态物质之一，尽管氧气输送和代谢率通常以1:1的方式相关。传统的代谢调节模型给出了这种行为的四种解释。此外，有一些证据表明存在通用的氧气传感器，这可能有助于我们摆脱这个矛盾。相比之下，支持细胞超微结构主导观点的人认为，细胞内灌注或对流是加速酶与底物相遇的主要方式，也是解释迄今为止最令人困惑的数据的一种方式：途径反应速率的变化与途径底物和中间体（包括氧气）浓度的变化之间明显缺乏相关性。这两种活细胞观点所体现的两极分化贯穿于整个代谢调节领域（并导致该领域沿着两条惊人独立的路径发展，它们之间的交流极少）。现在可能是两个领域之间进行相互交流的时候了。
