548-93-6Relevant articles and documents
Observing 3-hydroxyanthranilate-3,4-dioxygenase in action through a crystalline lens
Wang, Yifan,Liu, Kathy Fange,Yang, Yu,Davis, Ian,Liu, Aimin
, p. 19720 - 19730 (2020)
The synthesis of quinolinic acid from tryptophan is a critical step in the de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+) in mammals. Herein, the nonheme iron-based 3-hydroxyanthranilate-3,4-dioxygenase responsible for quinolinic acid production was studied by performing time-resolved in crystallo reactions monitored by UV-vis microspectroscopy, electron paramagnetic resonance (EPR) spectroscopy, and X-ray crystallography. Seven catalytic intermediates were kinetically and structurally resolved in the crystalline state, and each accompanies protein conformational changes at the active site. Among them, a monooxygenated, seven-membered lactone intermediate as a monodentate ligand of the iron center at 1.59-? resolution was captured, which presumably corresponds to a substrate-based radical species observed by EPR using a slurry of small-sized single crystals. Other structural snapshots determined at around 2.0-? resolution include monodentate and subsequently bidentate coordinated substrate, superoxo, alkylperoxo, and two metal-bound enol tautomers of the unstable dioxygenase product. These results reveal a detailed stepwise O-atom transfer dioxygenase mechanism along with potential isomerization activity that fine-tunes product profiling and affects the production of quinolinic acid at a junction of the metabolic pathway.
Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: Insights into the molecular basis of kynureninase substrate specificity
Lima, Santiago,Kumar, Sunil,Gawandi, Vijay,Momany, Cory,Phillips, Robert S.
body text, p. 389 - 396 (2009/10/01)
Homo sapiens kynureninase is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the hydrolytic cleavage of 3-hydroxykynurenine to yield 3-hydroxyanthranilate and L-alanine as part of the tryptophan catabolic pathway leading to the de novo biosynthesis of NAD+. This pathway results in quinolinate, an excitotoxin that is an NMDA receptor agonist. High levels of quinolinate have been correlated with the etiology of neurodegenerative disorders such as AIDS-related dementia and Alzheimer's disease. We have synthesized a novel kynureninase inhibitor, 3-hydroxyhippurate, cocrystallized it with human kynureninase, and solved the atomic structure. On the basis of an analysis of the complex, we designed a series of His- 102, Ser-332, and Asn-333 mutants. The H102W/N333T and H102W/S332G/N333T mutants showed complete reversal of substrate specificity between 3-hydroxykynurenine and L-kynurenine, thus defining the primary residues contributing to substrate specificity in kynureninases.
Decomposition of Cinnabarinic Acid by Hydrogen Peroxide
Manthey, Michael K.,Pyne, Stephen G.,Truscott, Roger J. W.
, p. 263 - 264 (2007/10/02)
The hydrogen peroxide-induced decomposition of cinnabarinic acid 2 has been examined.Two major compounds were found to arise from the decomposition; 3-hydroxyanthranilic acid 1, and an isomeric mixture of two novel hemiketals.
