3e9k
Crystal structure of Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex
Structural highlights
DiseaseKYNU_HUMAN Note=Xanthurenic aciduria manifesting as massive urinary excretion of large amounts of kynurenine, 3-hydroxykynurenine and xanthurenic acid has been observed in an individual carrying a homozygous missense change in KYNU (PubMed:17334708). The urinary pattern in the patient suggests kynureninase deficiency and a block in the conversion of kynurenine and 3-hydroxykynurenine to anthranilate and 3-hydroxyanthranilate, respectively.[HAMAP-Rule:MF_03017] FunctionKYNU_HUMAN Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-OHAA), respectively. Has a preference for the L-3-hydroxy form. Also has cysteine-conjugate-beta-lyase activity.[HAMAP-Rule:MF_03017] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHomo 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. Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity.,Lima S, Kumar S, Gawandi V, Momany C, Phillips RS J Med Chem. 2009 Jan 22;52(2):389-96. PMID:19143568[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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