Department of Plant and Microbial Biology, University of Minnesota Twin Cities, Saint Paul, MN, USA.
FEBS J. 2020 Apr;287(7):1343-1358. doi: 10.1111/febs.15284. Epub 2020 Mar 18.
Promiscuous enzymes and spontaneous chemical reactions can convert normal cellular metabolites into noncanonical or damaged metabolites. These damaged metabolites can be a useless drain on metabolism and may be inhibitory and/or reactive, sometimes leading to toxicity. Thus, mechanisms to prevent metabolite damage from occurring (metabolite damage preemption) or to convert damaged metabolites back to physiological forms (metabolite repair) are essential for sustained operation of metabolic networks. Some iconic examples of metabolite damage and its repair or preemption are associated with the tricarboxylic acid (TCA) cycle, and other metabolite damage control systems are likely to exist here due to the inherent promiscuity of TCA cycle enzymes and reactivity of TCA cycle intermediates. Here, we review known metabolite damage reactions and metabolite damage control systems associated with the TCA cycle. This includes a previously unrecognized metabolite damage control system - an oxaloacetate (OAA) enol-keto tautomerase activity that is 'built-in' to the TCA cycle. This activity is required to remove the highly inhibitory enol form of OAA and is likely to be critical for TCA cycle operation. By cataloging these instances, we show that metabolite damage and its repair or preemption is a prevalent feature of the TCA cycle and suggest many more metabolite damage control systems are likely to exist.
杂乱无章的酶和自发的化学反应可以将正常的细胞代谢物转化为非规范或受损的代谢物。这些受损的代谢物可能会对代谢造成无用的负担，并且可能具有抑制性和/或反应性，有时会导致毒性。因此，防止代谢物损伤发生的机制（代谢物损伤预防）或将受损代谢物转化回生理形式的机制（代谢物修复）对于代谢网络的持续运行是必不可少的。一些标志性的代谢物损伤及其修复或预防的例子与三羧酸 (TCA) 循环有关，由于 TCA 循环酶的固有杂乱性和 TCA 循环中间体的反应性，可能存在其他代谢物损伤控制系统。在这里，我们回顾了与 TCA 循环相关的已知代谢物损伤反应和代谢物损伤控制系统。这包括一个以前未被识别的代谢物损伤控制系统——内置于 TCA 循环中的草酰乙酸 (OAA) 烯醇-酮互变异构酶活性。该活性需要去除 OAA 的高度抑制性烯醇形式，并且可能对 TCA 循环的运行至关重要。通过对这些实例进行编目，我们表明代谢物损伤及其修复或预防是 TCA 循环的一个普遍特征，并表明可能存在更多的代谢物损伤控制系统。
