Alves R, Savageau M A
Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, Michigan 48109-0620 USA.
Biophys J. 2001 Mar;80(3):1174-85. doi: 10.1016/S0006-3495(01)76094-8.
It has been observed experimentally that most unbranched biosynthetic pathways have irreversible reactions near their beginning, many times at the first step. If there were no functional reasons for this fact, then one would expect irreversible reactions to be equally distributed among all positions in such pathways. Since this is not the case, we have attempted to identify functional consequences of having an irreversible reaction early in the pathway. We systematically varied the position of the irreversible reaction in model pathways and compared the resulting systemic behavior according to several criteria for functional effectiveness, using the method of mathematically controlled comparisons. This technique minimizes extraneous differences in systemic behavior and identifies those that are fundamental. Our results show that a pathway with an irreversible reaction located at the first step, and with all other reactions reversible, is on average better than an otherwise equivalent pathway with all reactions reversible, which in turn is on average better than an otherwise equivalent pathway with an irreversible reaction located at any step other than the first. Pathways with an irreversible first reaction and low concentrations of intermediates (one of the primary criteria for functional effectiveness) exhibit the following profile when compared to fully reversible pathways: changes in the concentration of intermediates in response to changes in the level of initial substrate are equally low, the robustness of the intermediate concentrations and of the flux is similar, the margins of stability are similar, flux is more responsive to changes in demand for end product, intermediate concentrations are less responsive to changes in demand for end product, and transient times are shorter. These results provide a functional rationale for the positioning of irreversible reactions at the beginning of unbranched biosynthetic pathways.
实验观察发现，大多数无分支的生物合成途径在其起始阶段附近有不可逆反应，很多时候是在第一步。如果这一事实没有功能上的原因，那么人们会预期不可逆反应会均匀分布在这些途径的所有位置。既然并非如此，我们就试图确定在途径早期存在不可逆反应的功能后果。我们在模型途径中系统地改变不可逆反应的位置，并根据几个功能有效性标准比较由此产生的系统行为，采用数学控制比较的方法。这种技术将系统行为中的无关差异降至最低，并识别出那些根本性的差异。我们的结果表明，一个在第一步有不可逆反应而其他所有反应均为可逆的途径，平均而言要优于一个所有反应均为可逆的等效途径，而后者又平均优于一个在第一步之外的任何步骤有不可逆反应的等效途径。与完全可逆的途径相比，具有不可逆第一步反应且中间产物浓度较低（功能有效性的主要标准之一）的途径呈现出以下特征：中间产物浓度随初始底物水平变化的变化同样较小，中间产物浓度和通量的稳健性相似，稳定性边际相似，通量对终产物需求变化的响应更灵敏，中间产物浓度对终产物需求变化的响应较不灵敏，且过渡时间更短。这些结果为在无分支生物合成途径起始阶段定位不可逆反应提供了功能上的理论依据。
