Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
Molecular Hepatology Laboratory, Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
Sci Rep. 2017 Dec 14;7(1):17559. doi: 10.1038/s41598-017-17979-7.
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: 291.5 μM and 26.3 μM, respectively), with estradiol, estradiol 3-sulfate and estrone sulfate being much weaker (IC > 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.
犬尿氨酸氨基转移酶（KAT）酶是依赖吡哆醛 5'-磷酸的同二聚体，可催化色氨酸代谢途径中犬尿氨酸不可逆地转氨生成犬尿酸（KYNA）。犬尿酸与精神分裂症等认知疾病有关，已有报道称，几种抑制剂可选择性地靶向 KAT-II，因为它主要负责人类大脑中犬尿酸的产生。不仅精神分裂症是一种性别二态性疾病，而且患有精神分裂症的女性其血清中的雌激素水平降低。雌激素也已知在犬尿氨酸途径中相互作用，因此探索这些相互作用可以更好地了解这种情况，并改善改善其影响的方法。酶抑制测定和结合研究表明，雌二醇二硫酸盐是 KAT-I 和 KAT-II 的强抑制剂（IC：分别为 291.5 μM 和 26.3 μM），而雌二醇、雌二醇 3-硫酸盐和雌酮硫酸盐则弱得多（IC>2 mM）。因此，雌激素水平可能决定大脑中犬尿酸的平衡。抑制测定结果和建模表明，雌二醇二硫酸盐中的 17-硫酸盐部分对于提高其作为抑制剂的效力非常重要，与雌二醇相比，抑制作用增加了约 10-100 倍。
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