ENZYMES OF QUINOLINIC ACID BIOSYNTHESIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。喹啉酸是烟酰胺腺嘌呤二核苷酸(NAD)的吡啶环的从头前体，NAD是所有生命系统中必不可少的氧化还原辅因子。喹啉酸有两种不同的生物合成途径。在原核生物中，喹啉酸主要由天冬氨酸和二羟丙酮磷酸形成；在真核生物中，它由色氨酸形成。然而，最近在细菌中发现了一种基于色氨酸的途径。我们的目标是对这两条途径中的酶进行结构表征，以帮助我们理解酶的机制。在基于色氨酸的途径中，我们的目标是2，3-色氨酸双加氧酶(TDO)，它是将色氨酸转化为N-甲酰犬尿氨酸途径中的第一个酶，以及3-羟基邻氨基苯甲酸-3，4-双加氧酶(HAD)，它是氧化3-羟基邻氨基苯甲酸酯生成喹啉酸的最后一个酶。在基于天冬氨酸的途径中，我们的重点是原核酶喹啉合酶(QS)，它催化亚氨基天冬氨酸和二羟丙酮磷酸缩合生成喹啉酸。这是该途径中最后一种具有结构和生化特征的酶。

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.