The biological cofactor nicotinamide adenine dinucleotide (NAD) is involved in many central metabolic reactions involving the transfer of one proton and two electrons. Depending of the organism, its precursor quinolinic acid (QA) is synthesized from tryptophan (like in humans) or from the condensation of dihydroxyacetone phosphate and iminoaspartate (in bacteria). The latter reaction, which is probably the oldest way to make QA, is catalyzed by the highly versatile enzyme NadA. Indeed, besides the condensation reaction, this protein catalyzes a dephosphorylation, an isomerization, a cyclization and two dehydration steps. The essential [4Fe-4S] cluster is bound at one end of the active site and is connected to the protein surface through a tunnel that can be open or closed depending on the nature (or absence) of the bound ligand.
Several crystal structures and the corresponding X-ray diffraction data for complexes of NadA with inhibitors, substrate analogs, at least one substrate (DHAP), product and potential intermediates of QA synthesis, are available from the Protein Data Bank. Based on a systematic analysis of these structures a coherent and comprehensive view of NadA catalysis is proposed in Coordination Chemistry Reviews by researchers from the Metallproteins group.
Structural basis for the catalytic activities of the multifunctional enzyme quinolinate synthase. Volbeda A, Fontecilla-Camps JC. Coordination Chemistry Reviews, Volume 417, 15 August 2020, 213370. https://doi.org/10.1016/j.ccr.2020.213370
Contact : Juan Fontecilla-Camps, Anne Volbeda