Targeting the Unique Mechanism of Bacterial 1-Deoxy-d-xylulose-5-phosphate Synthase.
Targeting the Unique Mechanism of Bacterial 1-Deoxy-d-xylulose-5-phosphate Synthase.
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DOI：
10.1021/acs.biochem.8b00548
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发表时间：
2018-07-24
期刊：
影响因子：
2.9
通讯作者：
Freel Meyers CL
中科院分区：
文献类型：
--
作者：
Bartee D;Freel Meyers CL
细菌代谢产物1-脱氧-D-木酮糖-5-磷酸(DXP)是细菌中枢代谢过程中的必需物质，可转化为类异戊二烯、硫胺素二磷酸(ThDP)和磷酸吡哆醛的从头合成。通过抑制DXP合成酶来阻止其生产是开发新型抗生素的一个有吸引力的策略。最近的工作表明，DxP合成酶利用了一种独特的随机顺序机制，要求丙酮酸衍生的C2-乳糖硫胺二磷酸(α-LThDP)、D-甘油醛-3-磷酸(D-GAP)与酶形成三元络合物，使其有别于所有其他已知的ThDP依赖的酶。在这里，我们描述了含有乙酰膦(AP)丙酮酸模拟物和模拟D-GAP的磷酸基的远端负电荷的双底物抑制剂的开发，旨在靶向在三元复合体中结合LThDP和D-GAP的DXP合成酶的独特形式。D-苯丙氨酸衍生的三氮唑乙酰膦(D-PheTrAP)是这一系列中最有效的抑制剂，它表现出慢-紧结合抑制，Ki*为90±10 nM，正向(K1)和反向(K2)异构化速率分别为1.1min和0.14min−1，DxP合成酶对哺乳动物丙酮酸脱氢酶的选择性高(>；15,000倍)。D-PheTrAP是迄今为止描述的最有效、最具选择性的DXP合成酶抑制剂，也是第一类专门为开发ThDP酶学中独特的E-LThDP-GAP三元复合体而设计的抑制剂。
The bacterial metabolite 1-deoxy-D-xyulose-5-phosphate (DXP) is essential in bacterial central metabolism feeding into isoprenoid, thiamin diphosphate (ThDP), and pyridoxal phosphate de novo biosynthesis. Halting its production through the inhibition of DXP synthase is an attractive strategy for the development of novel antibiotics. Recent work has revealed that DXP synthase utilizes a unique random sequential mechanism which requires ternary complex formation between pyruvate-derived C2α-lactylthiamin diphosphate (LThDP), D-glyceraldehyde-3-phosphate (D-GAP) and enzyme, setting it apart from all other known ThDP-dependent enzymes. Herein, we describe the development of bisubstrate inhibitors bearing an acetylphosphonate (AP) pyruvate mimic and a distal negative charge mimicking the phosphoryl group of D-GAP, designed to target the unique form of DXP synthase that binds LThDP and D-GAP in a ternary complex. A D-phenylalanine-derived triazole acetylphosphonate (D-PheTrAP) emerged as the most potent inhibitor in this series, displaying slow-tight-binding inhibition with Ki* of 90 ± 10 nM, forward (k1) and reverse (k2) isomerization rates of 1.1 and 0.14 min−1, respectively, and exquisite selectivity (>15,000-fold) for DXP synthase over mammalian pyruvate dehydrogenase. D-PheTrAP is the most potent, selective DXP synthase inhibitor described to date and represents the first inhibitor class designed specifically to exploit the unique E-LThDP-GAP ternary complex in ThDP enzymology.
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影响因子：
14.8
作者：
Gouzy, Alexandre;Larrouy-Maumus, Gerald;Wu, Ting-Di;Peixoto, Antonio;Levillain, Florence;Lugo-Villarino, Geanncarlo;Guerquin-Kern, Jean-Luc;de Carvalho, Luiz Pedro Sorio;Poquet, Yannick;Neyrolles, Olivier
通讯作者：
Neyrolles, Olivier
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
3.2
作者：
Bartee, David;Morris, Francine;Meyers, Caren L. Freel
通讯作者：
Meyers, Caren L. Freel
DOI：
10.1016/0005-2744(80)90186-2
发表时间：
1980-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
OBRIEN, TA;KLUGER, R;GENNIS, RB
通讯作者：
GENNIS, RB
影响因子：
3.6
作者：
Potter, Garrett T.;Jayson, Gordon C.;Gardiner, John M.
通讯作者：
Gardiner, John M.