Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid
Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid
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四氢生物蝶呤的生物合成是犬尿氨酸途径代谢物黄腐酸的潜在靶标
DOI：
10.1074/jbc.c115.680488
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发表时间：
2016-01-08
影响因子：
4.8
通讯作者：
Johnsson, Kai
中科院分区：
文献类型：
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作者：
Haruki, Hirohito;Hovius, Ruud;Johnsson, Kai
犬尿氨酸途径中的色氨酸代谢物被促炎细胞因子或糖皮质激素上调，并且与抗炎和免疫抑制活性相关。此外，它们在病理学如癌症、自身免疫性疾病和精神疾病中上调。犬尿氨酸途径代谢物如何引起这些作用的分子机制尚未完全了解。另一方面，促炎细胞因子也上调四氢生物蝶呤（BH 4）的量，这是一种合成几种神经递质和一氧化氮物质所必需的酶辅因子。在这里，我们表明，黄尿酸是一种有效的抑制剂sepiapterin还原酶（SPR），在从头BH 4合成的最后一种酶。结合到SPR活性位点的黄尿酸的晶体结构揭示了为什么在所有犬尿氨酸途径代谢物中黄尿酸是最有效的SPR抑制剂。我们的研究结果表明，犬尿氨酸途径上调导致的黄尿酸水平增加可以减弱BH4生物合成和BH4依赖性酶促反应，连接已知在炎症中高度上调的两个主要代谢途径。
Tryptophan metabolites in the kynurenine pathway are up-regulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.