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ACS Chem Biol. 2018 May 18;13(5):1209-1217. doi: 10.1021/acschembio.7b01104. Epub 2018 Apr 19.

Crystallographic Trapping of Reaction Intermediates in Quinolinic Acid Synthesis by NadA.

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Univ. Grenoble Alpes, CEA , CNRS, IBS, Metalloproteins Unit , F-38000 Grenoble , France.
Univ. Grenoble Alpes , CNRS, CEA, Laboratoire de Chimie et Biologie des Métaux, BioCat , 38000 , Grenoble , France.
Univ. Grenoble Alpes , CNRS, ICMG FR 2607, Département de Pharmacochimie Moléculaire , F-38041 , Grenoble , France.
Univ. Grenoble Alpes , CNRS, CEA, Laboratoire de Chimie et Biologie des Métaux, BioCE , 38000 , Grenoble , France.


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.

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