一个活细胞（如大肠杆菌）中上千种代谢物的浓度和流量的控制，是通过对酶浓度、活性和基质占据情况的调控实现的。嘧啶的从头生物合成按过去所报告的是在第一个“committed pathway step”（由“天冬氨酸氨甲酰基转移酶”催化）和前一个step（氨甲酰磷酸合成酶）被调控的。本文作者识别出一个新颖的调控策略（从UMP到尿嘧啶的一个溢出通道），大肠杆菌用它来避免过量嘧啶生物合成最终产物的积累。该过程类似于在“中心碳代谢”中看到的过程——在后者中，过量的糖代谢导致丙酮酸盐的积累，它们可以以乳酸盐、乙醇或乙酸盐的形式被排出。（生物谷Bioon.com）
生物谷推荐英文摘要：
Nature doi: 10.1038/nature12445
Pyrimidine homeostasis is accomplished by directed overflow metabolism
Marshall Louis Reaves, Brian D. Young, Aaron M. Hosios, Yi-Fan Xu & Joshua D. Rabinowitz
Cellular metabolism converts available nutrients into usable energy and biomass precursors. The process is regulated to facilitate efficient nutrient use and metabolic homeostasis. Feedback inhibition of the first committed step of a pathway by its final product is a classical means of controlling biosynthesis. In a canonical example, the first committed enzyme in the pyrimidine pathway in Escherichia coli is allosterically inhibited by cytidine triphosphate. The physiological consequences of disrupting this regulation, however, have not been previously explored. Here we identify an alternative regulatory strategy that enables precise control of pyrimidine pathway end-product levels, even in the presence of dysregulated biosynthetic flux. The mechanism involves cooperative feedback regulation of the near-terminal pathway enzyme uridine monophosphate kinase. Such feedback leads to build-up of the pathway intermediate uridine monophosphate, which is in turn degraded by a conserved phosphatase, here termed UmpH, with previously unknown physiological function. Such directed overflow metabolism allows homeostasis of uridine triphosphate and cytidine triphosphate levels at the expense of uracil excretion and slower growth during energy limitation. Disruption of the directed overflow regulatory mechanism impairs growth in pyrimidine-rich environments. Thus, pyrimidine homeostasis involves dual regulatory strategies, with classical feedback inhibition enhancing metabolic efficiency and directed overflow metabolism ensuring end-product homeostasis.
