Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae.
Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae.
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DOI：
10.1016/j.bmc.2009.12.050
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发表时间：
2010-02
影响因子：
3.5
通讯作者：
Silverman, Richard B.
中科院分区：
文献类型：
--
作者：
Kudoh, Takashi;Park, Chan Sun;Lefurgy, Scott T.;Sun, Meihao;Michels, Theodore;Leyh, Thomas S.;Silverman, Richard B.
关键词：
人类病原体肺炎链球菌的存活需要功能性甲羟戊酸途径，其产生异戊烯基二磷酸，类异戊二烯的基本构建单元。通过该途径的通量似乎在甲羟戊酸激酶（MK）步骤处受到调节，该步骤被该途径中的倒数第二化合物二磷酸甲羟戊酸（diphosphomevalonate，MK）强烈反馈抑制。人甲羟戊酸途径不受细菌调节，使细菌途径成为有吸引力的抗生素靶点。由于MK具有差的药物特性，是高度带电的，我们建议使用基于甲羟戊酸的未磷酸化的细胞可渗透的前药，所述甲羟戊酸将依次被MK和磷酸甲羟戊酸激酶（PMK）磷酸化以原位产生活性化合物。为了测试这种方法的局限性，我们合成了一系列C3-取代的甲羟戊酸类似物来探测MK和PMK活性位点的空间和电子要求。MK和PMK接受基板与多达两个额外的碳，表现出对小取代基的偏好。这一结果确立了在S. pneumoniae的细胞，并鉴定了几种类似物作为MK的抑制剂进行测试。两种酶所接受的底物包括甲羟戊酸环丙基、乙烯基和乙炔基类似物，当其二磷酸化时，可能是途径中下一个酶二磷酸甲羟戊酸脱羧酶的基于机制的灭活剂。
Survival of the human pathogen Streptococcus pneumoniae requires a functional mevalonate pathway, which produces isopentenyl diphosphate, the essential building block of isoprenoids. Flux through this pathway appears to be regulated at the mevalonate kinase (MK) step, which is strongly feedback-inhibited by diphosphomevalonate (DPM), the penultimate compound in the pathway. The human mevalonate pathway is not regulated by DPM, making the bacterial pathway an attractive antibiotic target. Since DPM has poor drug characteristics, being highly charged, we propose to use unphosphorylated, cell-permeable prodrugs based on mevalonate that will be phosphorylated in turn by MK and phosphomevalonate kinase (PMK) to generate the active compound in situ. To test the limits of this approach, we synthesized a series of C3-substituted mevalonate analogues to probe the steric and electronic requirements of the MK and PMK active sites. MK and PMK accepted substrates with up to two additional carbons, showing a preference for small substitutents. This result establishes the feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumoniae and identified several analogues to be tested as inhibitors of MK. Among the substrates accepted by both enzymes were cyclopropyl, vinyl, and ethynyl mevalonate analogues that, when diphosphorylated, might be mechanism-based inactivators of the next enzyme in the pathway, diphosphomevalonate decarboxylase.
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影响因子：
2.9
作者：
Andreassi, John L., II;Vetting, Matthew W.;Bilder, Patrick W.;Roderick, Steven L.;Leyh, Thomas S.
通讯作者：
Leyh, Thomas S.
影响因子：
64.8
作者：
Novak, R;Henriques, B;Tuomanen, E
通讯作者：
Tuomanen, E
影响因子：
2.9
作者：
Andreassi, JL;Dabovic, K;Leyh, TS
通讯作者：
Leyh, TS
影响因子：
8
作者：
Huang SS;Hinrichsen VL;Stevenson AE;Rifas-Shiman SL;Kleinman K;Pelton SI;Lipsitch M;Hanage WP;Lee GM;Finkelstein JA
通讯作者：
Finkelstein JA
影响因子：
3.9
作者：
Voynova NE;Fu Z;Battaile KP;Herdendorf TJ;Kim JJ;Miziorko HM
通讯作者：
Miziorko HM