Backbone and ILV methyl resonance assignments of E. coli thymidylate synthase bound to cofactor and a nucleotide analogue.
Backbone and ILV methyl resonance assignments of E. coli thymidylate synthase bound to cofactor and a nucleotide analogue.
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DOI：
10.1007/s12104-013-9482-6
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发表时间：
2014-04
影响因子：
0.9
通讯作者：
Lee AL
中科院分区：
文献类型：
--
作者：
Sapienza PJ;Lee AL
胸苷酸合成酶（TSase）是大多数生物体中从头合成胸苷一磷酸（dTMP）所需的62 kDa同源二聚体酶。这使得该酶成为抗癌和微生物抗生素药物的极好靶点。此外，TSase已显示出负协同性和半位点反应性。由于这些共同的原因，TSase被广泛研究，并且随着其通过多步催化循环的进展，对其动力学和结构有很多了解。最近，核磁共振（NMR）自旋弛豫已被证明在小模型系统中的酶功能的动力学的关键作用。这些研究提出了关于动力学如何影响具有更复杂反应坐标的较大酶的功能的问题。考虑到其大小、寡聚状态、协同性和作为药物靶标的状态，TSase是理想的候选物。在这里，作为自旋弛豫研究的先决条件，我们提出了从大肠杆菌绑定到底物类似物和辅因子的TSase的骨干和ILV甲基共振分配。
Thymidylate synthase (TSase) is a 62 kDa homodimeric enzyme required for de novo synthesis of thymidine monophosphate (dTMP) in most organisms. This makes the enzyme an excellent target for anticancer and microbial antibiotic drugs. In addition, TSase has been shown to exhibit negative cooperativity and half-the-sites reactivity. For these collective reasons, TSase is widely studied, and much is known about its kinetics and structure as it progresses through a multi-step catalytic cycle. Recently, nuclear magnetic resonance (NMR) spin relaxation has been instrumental in demonstrating the critical role of dynamics in enzyme function in small model systems. These studies raise questions about how dynamics affect function in larger enzymes with more complex reaction coordinates. TSase is an ideal candidate given its size, oligomeric state, cooperativity, and status as a drug target. Here, as a pre-requisite to spin relaxation studies, we present the backbone and ILV methyl resonance assignments of TSase from Escherichia coli bound to a substrate analogue and cofactor.
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