犬尿喹啉酸（Kynurenic acid）是唯一已知天然生成的神經(jīng)NMDA受體,，這種化合物在大腦中的數(shù)量異常與多種精神疾病有關(guān),，包括精神分裂癥。目前,，研究者發(fā)現(xiàn)了KYNA合成酶的3D結(jié)構(gòu),，該結(jié)果可能會(huì)使其成為新的藥物靶標(biāo),。
KYNA由一種名為 犬尿氨酸轉(zhuǎn)氨酶II （KAT-II）的酶合成,。弗吉尼亞科技大學(xué)的Jianyong Li及其同事們最近解析出了這種酶以及KAT-II與犬尿氨酸前體的復(fù)合物結(jié)構(gòu),，且解析結(jié)果分辨率很高。
解出的結(jié)構(gòu)有些令人驚訝,，KAT-II的前65個(gè)氨基酸以一種特定方式折疊,，使KAT-II的形狀與其他相關(guān)轉(zhuǎn)氨酶不同。論文作者認(rèn)為,，KAT-II代表了該轉(zhuǎn)氨酶家族中的一種新型亞類(lèi),。除了給合理的藥物開(kāi)發(fā)提供更詳細(xì)的分子模型，該酶的這種特殊結(jié)構(gòu)能使其成為理想的藥物靶點(diǎn),，因?yàn)橐运_(kāi)發(fā)出的藥物對(duì)其他相關(guān)酶類(lèi)的影響非常低,。
相關(guān)論文在線(xiàn)發(fā)表于2008年2月1日《生物化學(xué)雜志》（JBC）網(wǎng)站 (Vol. 283, No. 6)。 （來(lái)源：中科院廣州生物醫(yī)藥與健康研究院）
（《生物化學(xué)雜志》（JBC）,，Vol. 283, Issue 6, 3567-3573, February 8, 2008,，Qian Han, Jianyong Li）
生物谷推薦原始出處：
Originally published In Press as doi:10.1074/jbc.M708358200 on December 5, 2007
J. Biol. Chem., Vol. 283, Issue 6, 3567-3573, February 8, 2008
Crystal Structure of Human Kynurenine Aminotransferase II*
Qian Han, Howard Robinson, and Jianyong Li1
From the Department of Biochemistry, Virginia Tech University, Blacksburg, Virginia 24061 and the Biology Department, Brookhaven National Laboratory, Upton, New York 11973
Human kynurenine aminotransferase II (hKAT-II) efficiently catalyzes the transamination of knunrenine to kynurenic acid (KYNA). KYNA is the only known endogenous antagonist of N-methyl-D-aspartate (NMDA) receptors and is also an antagonist of 7-nicotinic acetylcholine receptors. Abnormal concentrations of brain KYNA have been implicated in the pathogenesis and development of several neurological and psychiatric diseases in humans. Consequently, enzymes involved in the production of brain KYNA have been considered potential regulatory targets. In this article, we report a 2.16Å crystal structure of hKAT-II and a 1.95Å structure of its complex with kynurenine. The protein architecture of hKAT-II reveals that it belongs to the fold-type I pyridoxal 5-phosphate (PLP)-dependent enzymes. In comparison with all subclasses of fold-type I-PLP-dependent enzymes, we propose that hKAT-II represents a novel subclass in the fold-type I enzymes because of the unique folding of its first 65 N-terminal residues. This study provides a molecular basis for future effort in maintaining physiological concentrations of KYNA through molecular and biochemical regulation of hKAT-II.
