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1.
Chem Commun (Camb) ; 55(26): 3725-3728, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30855610

RESUMO

Quinolinate synthase (NadA) is a [4Fe-4S] cluster-containing enzyme involved in the formation of quinolinic acid, the precursor of the essential NAD coenzyme. Here, we report the synthesis and activity of derivatives of the first inhibitor of NadA. Using multidisciplinary approaches we have investigated their action mechanism and discovered additional specific inhibitors of this enzyme.

2.
ACS Chem Biol ; 13(5): 1209-1217, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29641168

RESUMO

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.


Assuntos
Complexos Multienzimáticos/química , Ácido Quinolínico/metabolismo , Thermotoga maritima/enzimologia , Cristalografia por Raios X , Simulação de Acoplamento Molecular , Complexos Multienzimáticos/metabolismo , NAD/metabolismo , Conformação Proteica
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