Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives

The kynurenine aminotransferase (KAT) enzymes are pyridoxal 5′-phosphate-dependent homodimers that catalyse the irreversible transamination of kynurenine into kynurenic acid (KYNA) in the tryptophan metabolic pathway. Kynurenic acid is implicated in cognitive diseases such as schizophrenia, and seve...

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Published in:Scientific reports 2017-12, Vol.7 (1), p.17559-11, Article 17559
Main Authors: Jayawickrama, Gayan S., Nematollahi, Alireza, Sun, Guanchen, Gorrell, Mark D., Church, W. Bret
Format: Article
Language:English
Subjects:
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17β-Estradiol
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631/92/607/1172
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Acid production
Acids
Cognitive ability
Estrogens
Estrone
Humanities and Social Sciences
Isoenzymes
Kynurenic acid
Kynurenine-oxoglutarate transaminase
Mental disorders
multidisciplinary
Schizophrenia
Science
Science (multidisciplinary)
Sexual dimorphism
Sulfates
Tryptophan
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Summary:The kynurenine aminotransferase (KAT) enzymes are pyridoxal 5′-phosphate-dependent homodimers that catalyse the irreversible transamination of kynurenine into kynurenic acid (KYNA) in the tryptophan metabolic pathway. Kynurenic acid is implicated in cognitive diseases such as schizophrenia, and several inhibitors have been reported that selectively target KAT-II as it is primarily responsible for kynurenic acid production in the human brain. Not only is schizophrenia a sexually dimorphic condition, but women that have schizophrenia have reduced estrogen levels in their serum. Estrogens are also known to interact in the kynurenine pathway therefore exploring these interactions can yield a better understanding of the condition and improve approaches in ameliorating its effects. Enzyme inhibitory assays and binding studies showed that estradiol disulfate is a strong inhibitor of KAT-I and KAT-II (IC 50 : 291.5 μM and 26.3 μM, respectively), with estradiol, estradiol 3-sulfate and estrone sulfate being much weaker (IC 50  > 2 mM). Therefore it is possible that estrogen levels can dictate the balance of kynurenic acid in the brain. Inhibition assay results and modelling suggests that the 17-sulfate moiety in estradiol disulfate is very important in improving its potency as an inhibitor, increasing the inhibition by approximately 10–100 fold compared to estradiol.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-17979-7