二氢叶酸还原酶
大肠杆菌
反叶绿体
生物化学
新陈代谢
酶
化学
生物
抗代谢物
甲氨蝶呤
基因
免疫学
作者
Yun Kyung Kwon,Wenyun Lu,Eugene Melamud,Nurussaba Khanam,Andrew L. Bognar,Joshua D. Rabinowitz
摘要
Mass spectrometry technologies for measurement of cellular metabolism are opening new avenues to explore drug activity. Trimethoprim is an antibiotic that inhibits bacterial dihydrofolate reductase (DHFR). Kinetic flux profiling with (15)N-labeled ammonia in Escherichia coli reveals that trimethoprim leads to blockade not only of DHFR but also of another critical enzyme of folate metabolism: folylpoly-gamma-glutamate synthetase (FP-gamma-GS). Inhibition of FP-gamma-GS is not directly due to trimethoprim. Instead, it arises from accumulation of DHFR's substrate dihydrofolate, which we show is a potent FP-gamma-GS inhibitor. Thus, owing to the inherent connectivity of the metabolic network, falling DHFR activity leads to falling FP-gamma-GS activity in a domino-like cascade. This cascade results in complex folate dynamics, and its incorporation in a computational model of folate metabolism recapitulates the dynamics observed experimentally. These results highlight the potential for quantitative analysis of cellular metabolism to reveal mechanisms of drug action.
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