Active-site models unravel mechanism of enzymatic alkane activation
活性位点模型揭示了酶促烷烃活化的机制
基本信息
- 批准号:10711929
- 负责人:
- 金额:$ 18.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAlkanesApicalArchaeaBindingBiochemicalChargeChemicalsChemistryCoenzyme MComplementComplexCrystallizationDataDisulfidesEducational process of instructingEnergy MetabolismEnvironmentEnzymesEquilibriumGasesGastrointestinal DiseasesGoalsHealthHumanHydrocarbonsHydrogenHydrogen BondingIn SituLearningLigandsMeasurementMeasuresMediatingMedicineMetabolicMetabolic DiseasesMetabolismMethaneMethodsModelingNickelNitrogenOxidation-ReductionOxidoreductasePathway interactionsPeriodicityPharmacologic SubstancePhasePlanet EarthProcessReactionRegulationReportingResearchSpectrum AnalysisStructural ModelsStructureStructure-Activity RelationshipSulfhydryl CompoundsTestingThermodynamicsWaterWorkadductanalogcoenzyme Bcofactordensityexpectationfunctional mimicsgastrointestinalgut microbiotamethyl radicaloxidationsmall moleculetheoriesthioether
项目摘要
Project Summary
Archaea in the human gut express methyl-coenzyme M reductase (MCR) to catalyze the last step of
methanogenesis and the first step of the anaerobic oxidation of methane. These reactions occur at F430, a
nickel cofactor whose first coordination sphere — the ligands directly bound to it — includes the four nitrogen
atoms of a unique anionic macrocycle. This center reversibly cleaves the thioether methyl-coenzyme M (CoM–
SMe) to release methyl radical, which combines with thiol coenzyme B (HS–CoB) in the second coordination
sphere — the residues proximal to but not bonded to the active site — to liberate methane and the disulfide
CoM–S–S–CoB. The first and second coordination spheres of nickel in several MCR states are intractable,
which motivates us to synthesize tractable small molecules that recapitulate active-site features proposed for
these contentious states. Comparing data for models and MCR tells us how plausible these proposals are.
Our long-term goal is to synthesize high-fidelity models that help us understand how MCR makes and breaks
the C–H bonds in methane. Towards this goal, the objective of this project is to prepare, and spectroscopically
and chemically interrogate macrocyclic nickel complexes with very similar ligand environments to F430 in
different MCR states. The central hypothesis is that to mimic MCR spectroscopy a nickel complex needs a
high-fidelity first coordination sphere, while to mimic MCR function and cleave methane it further requires a
second-coordination-sphere radical. In preliminary work, we prepared and crystallized four-coordinate nickel
complexes of a readily tunable anionic macrocycle. Our density functional theory calculations predict that one
such complex should bind thiolate to mimic the first coordination sphere of F430 in the methane-cleaving step.
Further calculations predict that a related complex with a pendant thiyl radical near the thiolate is both plausible
and thermodynamically favored to cleave methane. The rationale is that tunable models will let us tease out
the motifs necessary for C–H activation. We will test our hypothesis by focusing on two specific aims. Aim 1:
Model the first coordination sphere of nickel in MCR to mimic spectroscopy and Aim 2: Model the second
coordination sphere of nickel in MCR to mimic function. Towards Aim 1 we will: (a) prepare and characterize
nickel complexes of anionic macrocycles, and (b) bind these complexes to water, thioether, thiolate, thiol,
methyl or hydride ligands. These ligands have been proposed to bind the MCR active site but evidence,
particularly for the last three ligands, is scarce, so our models will identify plausible first coordination spheres.
Towards Aim 2 we will: (a) further develop the nickel complexes to feature a thiolate and a proximal thiyl
radical, and (b) investigate the chemistry of this thiolate–thiyl species towards methane and other alkanes.
The macrocylic nickel complexes and their adducts will be the highest-fidelity synthetic models reported and
their activation of methane would be unprecedented for such nickel macrocycles. Overall, this work will
complement biochemical studies to fill in our mechanistic picture for MCR, a central metabolic enzyme.
项目概要
人类肠道中的古细菌表达甲基辅酶 M 还原酶(MCR)来催化最后一步
产甲烷和甲烷厌氧氧化的第一步这些反应发生在 F430,a。
镍辅助因子,其第一个配位球(直接与其结合的配体)包括四个氮
该中心可逆地裂解硫醚甲基辅酶 M (CoM–)。
SMe) 释放甲基自由基,与硫醇辅酶 B (HS–CoB) 进行第二配位结合
球体——靠近活性位点但未与活性位点结合的残基——释放甲烷和二硫化物
CoM–S–S–CoB 在几个 MCR 状态下镍的第一和第二配位层是棘手的,
这促使我们合成易于处理的小分子,这些小分子概括了提出的活性位点特征
比较模型和 MCR 的数据可以告诉我们这些建议的合理性。
我们的长期目标是合成高保真模型,帮助我们了解 MCR 的成败
为了实现这一目标,该项目的目标是通过光谱方法制备甲烷中的 C-H 键。
并以化学方式研究与 F430 配体环境非常相似的大环镍配合物
不同的 MCR 状态的中心假设是,为了模拟 MCR 光谱,镍配合物需要一个
高保真第一配位球,而为了模拟 MCR 功能并裂解甲烷,它还需要
在前期工作中,我们制备并结晶了四配位镍。
我们的密度泛函理论计算预测,一种易于调节的阴离子大环化合物。
这种复合物应结合硫醇盐以模拟甲烷裂解步骤中 F430 的第一个配位层。
进一步的计算预测,在硫醇盐附近具有侧垂硫基自由基的相关复合物都是合理的
热力学上有利于裂解甲烷,其基本原理是可调模型可以让我们弄清楚。
我们将通过关注两个具体目标来检验我们的假设。
对 MCR 中镍的第一个配位层进行建模以模拟光谱学,目标 2:对第二个进行建模
为实现目标 1,我们将:(a) 准备并表征 MCR 中镍的配位层。
阴离子大环的镍络合物,并且(b)将这些络合物与水、硫醚、硫醇盐、硫醇结合,
甲基或氢化物配体已被提议结合 MCR 活性位点,但有证据表明,
特别是对于最后三个配体,它是稀缺的,因此我们的模型将识别合理的第一配位球。
为了实现目标 2,我们将:(a) 进一步开发具有硫醇盐和近端硫基的镍配合物
自由基,以及(b)研究这种硫醇盐-硫基物质对甲烷和其他烷烃的化学作用。
大环镍配合物及其加合物将是已报道的最高保真度的合成模型
对于此类镍大环化合物来说,它们对甲烷的活化将是前所未有的。
补充生化研究,以填补我们对 MCR(一种中心代谢酶)的机制图景。
项目成果
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