ENZYMES OF QUINOLINIC ACID BIOSYNTHESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Quinolinic acid is the de novo precursor to the pyridine ring of nicotinamide adenine dinucleotide (NAD), an essential redox cofactor in all living systems. There are two different biosynthetic pathways to quinolinic acid. In prokaryotes, quinolinic acid is mostly formed from aspartate and dihydroxyacetone phosphate; in eukaryotes, it is formed from tryptophan. However, a tryptophan based pathway has been recently identified in bacteria. Our goal is to structurally characterize the enzymes in both pathways to help our understanding of the enzymatic mechanism. In the tryptophan based pathway, our targets are 2,3-tryptophan dioxygenase (TDO), which is the first enzyme in the pathway converting tryptophan to N-formyl kynurenine, and 3-hydroxyanthranilate-3,4-dioxygenase (HAD), which is the last enzyme oxidizing 3-hydroxyanthranilate to yield quinolinic acid. In the aspartate based pathway, our focus is on the prokaryotic enzyme quinolinate synthase (QS), which catalyzes the condensation of iminoaspartate and dihydroxyacetone phosphate to form quinolinic acid. This is the last enzyme in this pathway to be structurally and biochemically characterized.