Nature Chemical Biology：揭示一种临床抗菌剂新机制

甲氧苄氨嘧啶是一种抗菌素，主要用以治疗疟疾、呼吸道或尿道感染。最近，研究人员发现了这种药物有一种意想不到的多米诺骨牌效应，也就是说，它在药物的作用通道上抑制两种活性，新成果发表在《自然—化学生物学》期刊上。新工作揭示了这种临床药物的新机制，强调应深入研究药物的代谢通道，真正弄清楚药物的效果。
甲氧苄氨嘧啶通过抑制一种名为二氢叶酸还原酶(DHFR)的细菌酶来治疗疾病。通过同步测量一个细菌细胞中所有与叶酸相关的化学物质，Joshua Rabinowitz和同事发现，甲氧苄氨嘧啶不仅抑制了DHFR，而且还抑制了叶酸代谢中的其他酶。第二种酶不是由甲氧苄氨嘧啶直接抑制的，取而代之，DHFR的抑制导致二氢叶酸底物的堆积，并成为第二种酶的抑制剂。因此，甲氧苄氨嘧啶引发了酶抑制的级联反应。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Chemical Biology，doi:10.1038/nchembio.108 ，Yun Kyung Kwon，Joshua D Rabinowitz
A domino effect in antifolate drug action in Escherichia coli
Yun Kyung Kwon1, Wenyun Lu1, Eugene Melamud1, Nurussaba Khanam2, Andrew Bognar2 & Joshua D Rabinowitz1
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 15N-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--glutamate synthetase (FP--GS). Inhibition of FP--GS is not directly due to trimethoprim. Instead, it arises from accumulation of DHFR's substrate dihydrofolate, which we show is a potent FP--GS inhibitor. Thus, owing to the inherent connectivity of the metabolic network, falling DHFR activity leads to falling FP--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.
1 Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Washington Road, Princeton, New Jersey 08544, USA.2 Department of Microbiology, Medical Sciences Building #4383, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.