3E9K

Crystal structure of Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex

Summary for 3E9K

• Entry DOI: 10.2210/pdb3e9k/pdb
• Related: 1QZ9 2HZP
• Descriptor: Kynureninase, PYRIDOXAL-5'-PHOSPHATE, 3-Hydroxyhippuric acid, ... (4 entities in total)
• Functional Keywords: kynureninase, kynurenine-l-hydrolase, kynurenine hydrolase, pyridoxal-5'-phosphate, inhibitor complex, 3-hydroxy hippurate, 3-hydroxyhippuric acid, plp, pyridine nucleotide biosynthesis, pyridoxal phosphate, hydrolase
• Biological source: Homo sapiens
• Cellular location: Cytoplasm: Q16719
• Total number of polymer chains: 1
• Total formula weight: 52882.78

Authors

Lima, S.,Kumar, S.,Gawandi, V.,Momany, C.,Phillips, R.S. (deposition date: 2008-08-22, release date: 2008-12-09, Last modification date: 2023-08-30)

Primary citation

Lima, S.,Kumar, S.,Gawandi, V.,Momany, C.,Phillips, R.S.
Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity.
J.Med.Chem., 52:389-396, 2009

PubMed Abstract: 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.

PubMed: 19143568
DOI: 10.1021/jm8010806

Experimental method

X-RAY DIFFRACTION (1.7 Å)