甲氧芐氨嘧啶是一種抗菌素,，主要用以治療瘧疾、呼吸道或尿道感染,。最近,，研究人員發(fā)現(xiàn)了這種藥物有一種意想不到的多米諾骨牌效應(yīng)，也就是說,，它在藥物的作用通道上抑制兩種活性,，新成果發(fā)表在《自然—化學(xué)生物學(xué)》期刊上。新工作揭示了這種臨床藥物的新機制,，強調(diào)應(yīng)深入研究藥物的代謝通道,，真正弄清楚藥物的效果。
甲氧芐氨嘧啶通過抑制一種名為二氫葉酸還原酶(DHFR)的細(xì)菌酶來治療疾病。通過同步測量一個細(xì)菌細(xì)胞中所有與葉酸相關(guān)的化學(xué)物質(zhì),，Joshua Rabinowitz和同事發(fā)現(xiàn),，甲氧芐氨嘧啶不僅抑制了DHFR，而且還抑制了葉酸代謝中的其他酶,。第二種酶不是由甲氧芐氨嘧啶直接抑制的,，取而代之，DHFR的抑制導(dǎo)致二氫葉酸底物的堆積,，并成為第二種酶的抑制劑,。因此，甲氧芐氨嘧啶引發(fā)了酶抑制的級聯(lián)反應(yīng),。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
