金黄色葡萄球菌一氧化氮自由基诱导乳酸脱氢酶晶体结构解析和酶活性研究
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摘要
研究背景：金黄色葡萄球菌(Staphylococcus aureus)是最常见的革兰阳性致病菌，可以引起人体种类众多的感染。而且，随着抗生素的广泛使用，耐药性问题越来越严重。万古霉素作为治疗耐药金黄色葡萄球菌感染的最后一道防线，也出现了敏感性降低，甚至完全耐药的现象。其实，人类的自身先天免疫系统是有效抗击外来微生物入侵的第一道防线。其中一种重要的机制就是诱导性一氧化氮合成酶系统，其所合成的NO~*可以直接抑制微生物的有氧呼吸能量代谢，并抑制微生物的DNA复制。而金黄色葡萄球菌区别于其他非致病性葡萄球菌的一个主要特征，就是可以抵抗NO~*的毒性，在外源性NO~*压力下仍能生长和繁殖。其NO~*解毒机制一方面与黄素血红蛋白(hmp SACOL0220)行使的NO~*双氧化酶功能有关，可以将毒性NO~*转化为无毒的硝酸；另一方面与hmp同处于一个操纵子中的金黄色葡萄球菌乳酸脱氢酶-1(ldh-1 SACOL022)的诱导高表达密切相关。ldh-1与金黄色葡萄球菌中持续表达的同功酶ldh-2可以改变金黄色葡萄球菌在NO~*生存环境下细菌的能量代谢途径，从而使金黄色葡萄球菌可以在NO~*环境压力下正常生长和繁殖。研究思路：理论上ldh-1蛋白可以作为一个抗金黄色葡萄球菌的潜在靶点，任何对ldh-1具有选择性抑制作用的小分子物质，即只抑制金黄色葡萄球菌ldh-1但对人类的乳酸脱氢酶同功酶无明显抑制作用，就可能成为一种新的抗生素。研究方法：本研究首先将金黄色葡萄球菌中编码ldh-1和ldh-2的基因全长克隆到表达载体pET-28a中，大量表达重组蛋白，再利用重组蛋白的Histag，以亲和层析法和分子筛两步联合方法纯化重组蛋白纯度超过95％。进而，在不同理化条件下促使蛋白结晶，然后用所得到的单晶进行X射线衍射以解析蛋白的三维机构。研究结果：l；dh-1蛋白结晶，并收集高质量衍射数据。初步分析属于C2空间群，晶胞参数为a=131．36，b=74．362，c=103．243。ldh-1的结构最终可以被精修到2．2 (?)，R-Factor为17％，Rfree-factor为23．4％。使用分子置换法解析出其三维结构，分辨率达2．2埃。每个晶胞中有两个不对称的乳酸脱氢酶分子。每个ldh-1分子中包含两个结构域。大的结构域由22-160和248-264号氨基酸形成具有典型Rossmann特征的折叠。通过蛋白一级结构氨基酸序列的多重序列比对，活性位点的关键氨基酸序列保守，但活性环区上翘，使活性位点更加暴露。本研究还对ldh-1、ldh-2、人类骨骼肌ldh-A和心肌ldh-B的酶催化活性进行了比较，发现ldh-1与底物和辅酶的亲和性，和反应效率均明显高于人类的同功酶。通过对金黄色葡萄球菌中1dh结构、功能的研究，希望能以酶结构为基础，使用工作站筛选相关类别的小分子数据库，发现潜在的结构抑制剂。
Staphylococcus aureus (S.aureus)is one of the most prevalent pathogens tocause human infection.Pathogenic S.aureus is resistant to human innate immuneantimicrobe NO*,which is the first line of host defense depending on the mechanismthat NO* can inhibit bacterial respiration.Study indicated that S.aureus can changemetabolic state to survive from nitrosative stress,when a NO* inducible l-lactatedehydrogenase (ldh-1 SACOL0222)is expressed,which is also essential for thebacterial virulence.Thus,the inducible 1-lactate dehydrogenase in S.aureus wouldbecome a potential target for new class of antibiotics if we can find a selectiveinhibitor,which can potently inhibit S.aureus ldhl but shows much no inhibitionactivity against the human LDH isoforms.
To insight into its innate immune mechanism and to screen selective inhibitorbased structure for potential drug discovery,resoving the 3 dimentional structure ofldh1 from S.aureus is the key step.This thesis describes the l-lactate dehydrogenasestructure with 2.2 A resolution and the enzymatic kenetics study of converting lactateto pyruvate with NAD coenzyme.The crystals diffracted belonged to space group C2,and the unit-cell parameters are a=131.36,b=74.362,c=103.243.The final model ofldh-1 from S.aureus is refined to 2.18 A with R-factor and freer-factor of 17% and23.4% respectively.There are two molecules per asymmetric unit (shown in Figure 3).There are two domains:the larger with a“Rossmann”type fold formed by residue22-160 and 248-264.Active site loop of Idh-1 from S.aureus is highly conserved(96-108)between spcies,however,adopts a more open conformation,which increasethe volume of the active site cleft in ldh-1 from S.aureus.From enzymetic keneticsstudy,significant increase of Km and Kcat feetures ldh-1 from human isoforms.
Staphylococcus aureus (S.aureus)is one of the most prevalent pathogens tocause human infection.Pathogenic S.aureus is resistant to human innate immuneantimicrobe NO*,which is the first line of host defense depending on the mechanismthat NO* can inhibit bacterial respiration.Study indicated that S.aureus can changemetabolic state to survive from nitrosative stress,when a NO* inducible l-lactatedehydrogenase (ldh-1 SACOL0222)is expressed,which is also essential for thebacterial virulence.Thus,the inducible 1-lactate dehydrogenase in S.aureus wouldbecome a potential target for new class of antibiotics if we can find a selectiveinhibitor,which can potently inhibit S.aureus ldhl but shows much no inhibitionactivity against the human LDH isoforms.
To insight into its innate immune mechanism and to screen selective inhibitorbased structure for potential drug discovery,resoving the 3 dimentional structure ofldh1 from S.aureus is the key step.This thesis describes the l-lactate dehydrogenasestructure with 2.2 A resolution and the enzymatic kenetics study of converting lactateto pyruvate with NAD coenzyme.The crystals diffracted belonged to space group C2,and the unit-cell parameters are a=131.36,b=74.362,c=103.243.The final model ofldh-1 from S.aureus is refined to 2.18 A with R-factor and freer-factor of 17% and23.4% respectively.There are two molecules per asymmetric unit (shown in Figure 3).There are two domains:the larger with a“Rossmann”type fold formed by residue22-160 and 248-264.Active site loop of Idh-1 from S.aureus is highly conserved(96-108)between spcies,however,adopts a more open conformation,which increasethe volume of the active site cleft in ldh-1 from S.aureus.From enzymetic keneticsstudy,significant increase of Km and Kcat feetures ldh-1 from human isoforms.
引文
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[1] Diekema DJ, P. M., Schmitz FJ, Smayevsky J, et. Al. (2001). "Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999." [J] Clin Infect Dis. 2001 May 15;32 Suppl 2:S114-32.
[2] Kluytmans J, v. B. A., Verbrugh H. (1997). "Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks." [J] Clin Microbiol Rev. 1997 Jul;10(3):505-20.
[3] Lowy, F. (1998). "Staphylococcus aureus infections." [J] Engl J Med. 1998 Aug 20;339(8):520-32..
[4] Moreillon P, Q. Y.-A., Glauser M. (2005). "Staphyloccocus aureus." Douglas and Bennett's principles and practices of infectious diseases. 6th edition Vol. 2. p2312-51. [M]. Elsevier Publisher.
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