Hochachka P W
Department of Zoology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
J Exp Biol. 2003 Jun;206(Pt 12):2001-9. doi: 10.1242/jeb.00402.
Two views currently dominate experimental approaches to metabolic regulation. The first, let us call it Model 1, assumes that cells behave like a watery bag of enzymes. The alternative Model 2, however, assumes that 3-dimensional order and structure constrain metabolite behavior. A major problem in cell metabolism is determining why essentially all metabolite concentrations are remarkably stable (homeostatic) over large changes in pathway fluxes-for convenience, this is termed the [s] stability paradox. During large-scale transitions from maintenance metabolic rates to maximally activated work, contrasting demands of intracellular homeostasis versus metabolic regulation obviously arise. Data accumulated over the last 3-4 decades now make it clear that the demands of homeostasis prevail: during rest-work transitions, metabolites such as ATP and O(2) are notably and rigorously homeostatic; other intermediates usually do not vary by more than 0.5- to threefold over the resting condition. This impressive homeostasis is maintained despite changes in pathway fluxes that can exceed two orders of magnitude. Classical or Model 1 approaches to this problem can explain metabolite homeostasis, but the mechanisms for each metabolite, each enzyme locus, are necessarily specific. Thus Model 1 approaches basically do not provide a global explanation for the [s] stability paradox. Model 2 takes a different tack and assumes that an intracellular convection system acts as an over-riding 'assist' mechanism for facilitating enzyme-substrate encounter. Model 2 postulates that intracellular movement and convection are powered by macromolecular motors (unconventional myosins, dyneins, kinesin) running on actin or tubulin tracks. For fast and slow muscle fibers, microfilaments are concentrated near the periphery (where convection may be most important), but also extend throughout the actomyosin contractile apparatus both in horizontal and vertical dimensions. To this point in the development of the field, Model 1 and Model 2 approaches have operated as 'two solitudes', each considering the other incompatible with its own experimental modus operandi. In order to finally assemble a model that can sensibly explain a realistic working range of metabolic systems, opening of channels of communication between the above two very differing views of metabolic regulation would seem to be the requirement for the future.
目前有两种观点主导着代谢调节的实验方法。第一种，我们称之为模型1，它假定细胞的行为就像一个装满酶的水袋。然而，另一种模型2则假定三维秩序和结构会限制代谢物的行为。细胞代谢中的一个主要问题是要确定为什么在途径通量发生大幅变化时，基本上所有代谢物的浓度都能显著稳定（稳态）——为方便起见，这被称为[s]稳定性悖论。在从维持代谢率到最大激活工作状态的大规模转变过程中，细胞内稳态与代谢调节的不同需求显然会出现。过去三四十年积累的数据现在清楚地表明，稳态需求占主导：在静息 - 工作转变期间，诸如ATP和O₂等代谢物具有显著且严格的稳态；其他中间产物在静息状态下的变化通常不超过0.5倍至三倍。尽管途径通量的变化可能超过两个数量级，但这种令人印象深刻的稳态仍得以维持。针对这个问题的经典或模型1方法可以解释代谢物的稳态，但每种代谢物、每个酶位点的机制必然是特定的。因此，模型1方法基本上无法为[s]稳定性悖论提供一个全局性的解释。模型2则采取了不同的策略，它假定细胞内对流系统作为一种首要的“辅助”机制，以促进酶与底物的相遇。模型2假设细胞内的运动和对流是由在肌动蛋白或微管蛋白轨道上运行的大分子马达（非常规肌球蛋白、动力蛋白、驱动蛋白）驱动的。对于快肌纤维和慢肌纤维，微丝集中在周边附近（对流可能在此处最为重要），但也在水平和垂直方向上贯穿整个肌动球蛋白收缩装置。到目前为止，在该领域的发展过程中，模型1和模型2方法一直各自为政，每种方法都认为另一种方法与其自身的实验操作方式不相容。为了最终构建一个能够合理地解释代谢系统实际工作范围的模型，开启上述两种截然不同的代谢调节观点之间的沟通渠道似乎是未来的必要条件。
