Guo Rey-Ting, Cao Rong, Liang Po-Huang, Ko Tzu-Ping, Chang Tao-Hsin, Hudock Michael P, Jeng Wen-Yih, Chen Cammy K-M, Zhang Yonghui, Song Yongcheng, Kuo Chih-Jung, Yin Fenglin, Oldfield Eric, Wang Andrew H-J
Taiwan International Graduate Program, Institute of Biological Chemistry, Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan.
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. doi: 10.1073/pnas.0702254104. Epub 2007 May 29.
Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
双膦酸盐药物（如福善美和择泰）被认为主要通过抑制法尼基二磷酸合酶（FPPS）起作用，导致小GTP酶的异戊二烯化减少。在此，我们表明一些双膦酸盐还可以抑制香叶基香叶基二磷酸合酶（GGPPS）以及十一异戊烯基二磷酸合酶（UPPS），后者作为抗菌治疗靶点的一种顺式异戊二烯基转移酶备受关注。我们关于GGPPS（10个结构）的结果表明存在三个双膦酸盐结合位点，由FPP或异戊烯基二磷酸底物结合位点以及GGPP产物或抑制剂结合位点组成。在UPPS中，总共存在四个结合位点（五个结构中）。这些结果具有普遍意义，因为它们不仅提供了GGPPS和UPPS抑制剂复合物（潜在的重要药物靶点）的首个结构，还揭示了在FPPS抑制中未见的显著广泛的结合模式。
