METABOLIC SPECIFICITY OF METHYLTHIOCOFORMYCIN FOR MALARIAL ADENOSINE DEAMINASE
甲硫基辅霉素对疟疾腺苷脱氨酶的代谢特异性
基本信息
- 批准号:8169275
- 负责人:
- 金额:$ 0.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2011-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adenine NucleotidesAdenosineAffinityBindingBinding SitesCatalytic DomainCoformycinComplexComputer Retrieval of Information on Scientific Projects DatabaseEnzymesErythrocytesFundingGrantHumanHydrogen BondingHydroxyl RadicalHypoxanthinesInstitutionKineticsMetabolicMutagenesisPathway interactionsPentostatinPlasmodiumPlasmodium falciparumPlasmodium gallinaceumPlasmodium vivaxPurine NucleotidesPurinesReportingResearchResearch PersonnelResourcesSourceSpecificityStructureSubstrate SpecificityUnited States National Institutes of HealthWateradenosine deaminaseanalogbasepurine
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
Plasmodium falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation in Plasmodium falciparum. Methylthioadenosine (MTA) is one of purine nucleotide substrates for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation. In this study, we report the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin that reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
恶性疟原虫是嘌呤营养缺陷型,需要次黄嘌呤作为关键的代谢前体。红细胞腺嘌呤核苷酸是嘌呤前体的来源,使腺苷脱氨酶(ADA)成为恶性疟原虫次黄嘌呤形成途径中的关键酶。甲基硫代腺苷(MTA)是大多数疟疾ADA的嘌呤核苷酸底物之一,而不是人ADA的底物。疟疾ADA的催化位点特异性允许甲硫共形霉素(MT-共形霉素)作为疟原虫特异性过渡态类似物,对人ADA具有低亲和力[泰勒,P.C.,Taylor,E.一、弗罗利希河G. G.,和Schramm,V.L.等人(2007)J. Am. 129,6872-6879]。疟疾ADA中MTA和MT-共形霉素特异性的结构基础是推测的主题。在这项研究中,我们报告的ADA从间日疟原虫(PvADA)的晶体结构与MT-共福霉素的复合物,揭示了一个前所未有的结合几何形状的5 '-甲基硫代核糖基基团的疟疾ADA。与疟疾ADA与腺苷或脱氧coformycin的复合物相比,5 '-甲基硫代核糖基旋转130度。Asp 172和MT-共形霉素的3 '-羟基之间的氢键网络对于识别5'-甲基硫代核糖基是必需的。当MT-共形霉素结合时,水占据5 '-羟基结合位点。Asp 172的突变破坏了MTA和MT-共福霉素的底物特异性。PvADA的动力学、致突变性和结构分析以及其他五种疟原虫ADA的动力学分析确立了其对MTA和MT-共福霉素特异性的独特结构基础。鸡疟原虫ADA不使用MTA作为底物,不被MT-共福霉素抑制,并且缺失Asp 172。
项目成果
期刊论文数量(0)
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