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Crystallographic Trapping of Reaction Intermediates in Quinolinic Acid Synthesis by NadA
ACS Chemical Biology ( IF 4 ) Pub Date : 2018-04-11 00:00:00 , DOI: 10.1021/acschembio.7b01104
Anne Volbeda 1 , Jaione Saez Cabodevilla 2, 3 , Claudine Darnault 1 , Océane Gigarel 1 , Thi-Hong-Lien Han 2 , Oriane Renoux 1 , Olivier Hamelin 4 , Sandrine Ollagnier-de-Choudens 2 , Patricia Amara 1 , Juan C. Fontecilla-Camps 1
Affiliation  

NadA is a multifunctional enzyme that condenses dihydroxyacetone phosphate (DHAP) with iminoaspartate (IA) to generate quinolinic acid (QA), the universal precursor of the nicotinamide adenine dinucleotide (NAD(P)) cofactor. Using X-ray crystallography, we have (i) characterized two of the reaction intermediates of QA synthesis using a “pH-shift” approach and a slowly reacting Thermotoga maritima NadA variant and (ii) observed the QA product, resulting from the degradation of an intermediate analogue, bound close to the entrance of a long tunnel leading to the solvent medium. We have also used molecular docking to propose a condensation mechanism between DHAP and IA based on two previously published Pyrococcus horikoshi NadA structures. The combination of reported data and our new results provide a structure-based complete catalytic sequence of QA synthesis by NadA.

中文翻译:

NadA合成喹啉酸中反应中间体的晶体学陷阱

NadA是一种多功能酶,可使磷酸二羟基丙酮磷酸酯(DHAP)与亚氨基天冬氨酸(IA)缩合生成喹啉酸(QA),后者是烟酰胺腺嘌呤二核苷酸(NAD(P))辅助因子的通用前体。使用X射线晶体学,我们(i)使用“ pH偏移”方法和缓慢反应的马氏球菌NadA变体表征了QA合成的两种反应中间体,并且(ii)观察到由于QA降解而产生的QA​​产物。中间类似物,绑定在通向溶剂介质的长隧道的入口附近。我们还使用了分子对接技术,基于之前发表的两个火球菌,提出了DHAP和IA之间的缩合机理。NadA结构。报告数据和我们的新结果的结合提供了NadA进行QA合成的基于结构的完整催化序列。
更新日期:2018-04-11
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