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Structural and Functional Studies of Bacillus anthracis Enzymes in de novo Purine Synthesis.

機(jī)譯：從頭合成嘌呤中炭疽桿菌酶的結(jié)構(gòu)和功能研究。

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The de novo purine biosynthesis is an essential life sustaining process in many organisms, including bacterial pathogens. My work investigates the structural and functional properties of enzymes from this pathway in Bacillus anthracis (Ba) towards the identification of antimicrobials. The first enzyme I studied was PurK, which carboxylates aminoimidazole ribonucleotide (AIR), with bicarbonate in the presence of ATP, to N5-carboxyaminoimidazole ribonucleotide (N5-CAIR). PurK is unique to prokaryotes and lower eukaryotes. Divergence at this step in the pathway makes it an appealing target for antimicrobial development. I used x-ray crystallography to solve the structure of BaPurK. My work also produced several ligand-bound BaPurK structures; of which included bicarbonate in the active site, a first for any PurK structure. Based on these structures, a reaction mechanism was proposed. The second enzyme I focused on was PurC. BaPurC catalyzes the conversion of carboxyaminoimidazole ribonucleotide (CAIR) and aspartate (L-Asp) to succinoaminoimidazolecarboxamide ribonucleotide (SAICAR), with the use of ATP. Studies focused on the large difference in the purification yield between Bacillus anthracis and Streptococcus pneumoniae PurC. Although their amino acid sequences are very similar the recombinant protein yields differed by more than 10-fold. Results from biophysical studies with CD and fluorescence spectroscopies, and molecular modeling suggest that the variances in exposed hydrophobic surfaces are the cause of the difference in purification yield. BaPurC was targeted in high throughput screening, using malachite green, a common phosphate detection assay, in effort to find antimicrobials that inhibit this enzyme from Bacillus anthracis. A set of hit molecules was obtained from the screening of activity inhibition. While analyzing the data an unusual trend appeared in the controls of the assay, further investigation of this event reveals that PurC exhibits substrate-independent ATPase activity, which provides insights into the reaction mechanism.
機(jī)譯：從頭開始的嘌呤生物合成是許多生物（包括細(xì)菌病原體）中必不可少的生命維持過程。我的工作調(diào)查了炭疽芽孢桿菌（Ba）中此途徑中通往抗微生物藥鑒定的酶的結(jié)構(gòu)和功能特性。我研究的第一個(gè)酶是PurK，它在ATP存在的情況下用碳酸氫鹽將氨基咪唑核糖核苷酸（AIR）羧化為N5-羧基氨基咪唑核糖核苷酸（N5-CAIR）。 PurK是原核生物和低等真核生物所獨(dú)有的。該途徑這一步驟的差異性使其成為抗微生物發(fā)展的誘人目標(biāo)。我使用X射線晶體學(xué)來解決BaPurK的結(jié)構(gòu)。我的工作還產(chǎn)生了幾個(gè)配體結(jié)合的BaPurK結(jié)構(gòu)。其中在活性位點(diǎn)中包含碳酸氫鹽，這是任何PurK結(jié)構(gòu)的首創(chuàng)。基于這些結(jié)構(gòu)，提出了一種反應(yīng)機(jī)理。我關(guān)注的第二種酶是PurC。 BaPurC使用ATP催化羧氨基咪唑核糖核苷酸（CAIR）和天冬氨酸（L-Asp）轉(zhuǎn)化為琥珀酰胺基咪唑羧酰胺核糖核苷酸（SAICAR）。研究集中在炭疽芽孢桿菌和肺炎鏈球菌PurC的純化產(chǎn)率上有很大差異。盡管它們的氨基酸序列非常相似，但重組蛋白的產(chǎn)量相差十倍以上。 CD和熒光光譜的生物物理研究結(jié)果以及分子模型表明，疏水表面暴露的差異是純化產(chǎn)率差異的原因。 BaPurC的目標(biāo)是使用孔雀石綠（一種常見的磷酸鹽檢測(cè)測(cè)定法）進(jìn)行高通量篩選，以尋找可抑制炭疽桿菌中抑制該酶的抗菌劑。從活性抑制的篩選中獲得了一組命中分子。在分析數(shù)據(jù)時(shí)，分析控件中出現(xiàn)了異常的趨勢(shì)，對(duì)此事件的進(jìn)一步研究表明，PurC表現(xiàn)出與底物無關(guān)的ATPase活性，從而提供了對(duì)反應(yīng)機(jī)理的認(rèn)識(shí)。

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  • 作者

    Tuntland, Micheal L.;

  • 作者單位

    University of Illinois at Chicago.;

  • 授予單位 University of Illinois at Chicago.;
  • 學(xué)科 Chemistry.
  • 學(xué)位 Ph.D.
  • 年度 2015
  • 頁(yè)碼 151 p.
  • 總頁(yè)數(shù) 151
  • 原文格式 PDF
  • 正文語(yǔ)種 eng
  • 中圖分類 遙感技術(shù);
  • 關(guān)鍵詞

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