一個活細(xì)胞（如大腸桿菌）中上千種代謝物的濃度和流量的控制,，是通過對酶濃度、活性和基質(zhì)占據(jù)情況的調(diào)控實現(xiàn)的,。嘧啶的從頭生物合成按過去所報告的是在第一個“committed pathway step”（由“天冬氨酸氨甲?；D(zhuǎn)移酶”催化）和前一個step（氨甲酰磷酸合成酶）被調(diào)控的。本文作者識別出一個新穎的調(diào)控策略（從UMP到尿嘧啶的一個溢出通道）,，大腸桿菌用它來避免過量嘧啶生物合成最終產(chǎn)物的積累,。該過程類似于在“中心碳代謝”中看到的過程——在后者中，過量的糖代謝導(dǎo)致丙酮酸鹽的積累，它們可以以乳酸鹽,、乙醇或乙酸鹽的形式被排出,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
