wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs.
wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs.
复制标题
wALADin 苯并咪唑差异性地调节胆色素原合酶直系同源物的功能。
DOI：
10.1021/jm401785n
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发表时间：
2014
影响因子：
7.3
通讯作者：
Pfarr,KennethM
中科院分区：
文献类型：
--
作者：
Lentz,ChristianS;Halls,VictoriaS;Hannam,JeffreyS;Strassel,Silke;Lawrence,SarahH;Jaffe,EileenK;Famulok,Michael;Hoerauf,Achim;Pfarr,KennethM
血红素生物合成酶胆色素原合酶（PBGS）是多种人类病原体的潜在药物靶点。 wALADin1 苯并咪唑已成为针对丝虫沃尔巴克氏菌内细菌的物种选择性 PBGS 抑制剂。在本研究中，我们系统地测试了 wALADins 与来自细菌、原生动物、后生动物和植物的 PBGS 直系同源物，以阐明其抑制谱。然而，wALADin1 对不同 PBGS 直向同源物的作用并不限于抑制：wALADin1 刺激了几种直向同源物；其他人则不受影响。我们证明 wALADins 通过有利于低活性寡聚物介导的抑制作用来变构调节 PBGS 同寡聚平衡，而 5-氨基乙酰丙酸、Mg2+ 或 K+ 稳定高活性寡聚物。 根据这些因素和 pH 值，wALADin1 可以抑制或刺激铜绿假单胞菌 PBGS。我们已经定义了负责抑制或刺激的 wALADin 化学型，促进了定制 PBGS 调节剂的设计，其潜在应用为抗菌剂、除草剂或卟啉病药物。
The heme biosynthesis enzyme porphobilinogen synthase (PBGS) is a potential drug target in several human pathogens. wALADin1 benzimidazoles have emerged as species-selective PBGS inhibitors againstWolbachiaendobacteria of filarial worms. In the present study, we have systematically tested wALADins against PBGS orthologs from bacteria, protozoa, metazoa, and plants to elucidate the inhibitory spectrum. However, the effect of wALADin1 on different PBGS orthologs was not limited to inhibition: several orthologs were stimulated by wALADin1; others remained unaffected. We demonstrate that wALADins allosterically modulate the PBGS homooligomeric equilibrium with inhibition mediated by favoring low-activity oligomers, while 5-aminolevulinic acid, Mg2+, or K+stabilized high-activity oligomers.Pseudomonas aeruginosaPBGS could be inhibited or stimulated by wALADin1 depending on these factors and pH. We have defined the wALADin chemotypes responsible for either inhibition or stimulation, facilitating the design of tailored PBGS modulators for potential application as antimicrobial agents, herbicides, or drugs for porphyric disorders.