Transient Formation of a Second Active Site Cavity during Quinolinic Acid Synthesis by NadA - Groupe Métalloprotéines / Metalloproteins Group (IBS-METALLO)
Article Dans Une Revue ACS Chemical Biology Année : 2021

Transient Formation of a Second Active Site Cavity during Quinolinic Acid Synthesis by NadA

Hind Basbous
  • Fonction : Auteur
Anne Volbeda
Patricia Amara
Sandrine Ollagnier de Choudens
  • Fonction : Auteur correspondant
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Résumé

: Quinolinate synthase, also called NadA, is a [4Fe-4S]-containing enzyme that uses what is probably the oldest pathway to generate quinolinic acid (QA), the universal precursor of the biologically essential cofactor nicotinamide adenine dinucleotide (NAD). Its synthesis comprises the condensation of dihydroxyacetone phosphate (DHAP) and iminoaspartate (IA), which involves dephosphorylation, isomerization, cyclization, and two dehydration steps. The convergence of the three homologous domains of NadA defines a narrow active site that contains a catalytically essential [4Fe-4S] cluster. A tunnel, which can be opened or closed depending on the nature (or absence) of the bound ligand, connects this cofactor to the protein surface. One outstanding riddle has been the observation that the so far characterized active site is too small to bind IA and DHAP simultaneously. Here, we have used site-directed mutagenesis, X-ray crystallography, functional analyses, and molecular dynamics simulations to propose a condensation mechanism that involves the transient formation of a second active site cavity to which one of the substrates can migrate before this reaction takes place.
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Dates et versions

hal-03383427 , version 1 (18-10-2021)

Identifiants

Citer

Hind Basbous, Anne Volbeda, Patricia Amara, Roman Rohac, Lydie Martin, et al.. Transient Formation of a Second Active Site Cavity during Quinolinic Acid Synthesis by NadA. ACS Chemical Biology, 2021, 16 (11), pp.2423-2433. ⟨10.1021/acschembio.1c00541⟩. ⟨hal-03383427⟩
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