Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, GA 30303, United States.
Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, GA 30303, United States.
Arch Biochem Biophys. 2014 Feb 15;544:18-26. doi: 10.1016/j.abb.2013.11.009. Epub 2013 Dec 1.
L-Tryptophan is an essential amino acid for mammals. It is utilized not only for protein synthesis but also for the biosynthesis of serotonin and melatonin by the serotonin pathway as well as nicotinamide adenine dinucleotide by the kynurenine pathway. Although the kynurenine pathway is responsible for the catabolism of over 90% of l-tryptophan in the mammalian intracellular and extracellular pools, the scientific field was dominated in the last century by studies of the serotonin pathway, due to the physiological significance of the latter's catabolic intermediates and products. However, in the past decade, the focus gradually reversed as the link between the kynurenine pathway and various neurodegenerative disorders and immune diseases is increasingly highlighted. Notably, the first step of this pathway, which is catalyzed by heme-dependent dioxygenases, has been proven to be a potential target for immune regulation and cancer treatment. A thorough understanding of the intriguing chemistry of the heme-dependent dioxygenases may yield insight for the drug discovery of these prevalent illnesses. In this review, we survey enzymatic and mechanistic studies, initially started by Kotake and Masayama over 70 years ago, at the molecular level on the heme-dependent tryptophan dioxygenation reactions.
L-色氨酸是哺乳动物的必需氨基酸。它不仅用于蛋白质合成，还通过色氨酸途径用于 5-羟色胺和褪黑素的生物合成，以及通过犬尿氨酸途径用于烟酰胺腺嘌呤二核苷酸的生物合成。尽管犬尿氨酸途径负责分解哺乳动物细胞内和细胞外池中的超过 90%的 L-色氨酸，但在上个世纪，由于后者的代谢中间产物和产物的生理意义，科学领域主要集中在色氨酸途径的研究上。然而，在过去的十年中，随着犬尿氨酸途径与各种神经退行性疾病和免疫性疾病之间的联系逐渐得到强调，研究重点逐渐发生了转变。值得注意的是，该途径的第一步由血红素依赖性加氧酶催化，已被证明是免疫调节和癌症治疗的潜在靶点。深入了解血红素依赖性加氧酶的有趣化学性质，可能为这些常见疾病的药物发现提供新的思路。在这篇综述中，我们在分子水平上综述了 Kotake 和 Masayama 早在 70 多年前就开始的酶学和机制研究，探讨了血红素依赖性色氨酸加氧酶反应。
