Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, Colorado, USA.
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Aurora, Colorado, USA.
FASEB J. 2018 Mar;32(3):1265-1280. doi: 10.1096/fj.201700586R. Epub 2018 Jan 3.
Cystathionine β-synthase-deficient homocystinuria (HCU) is a poorly understood, life-threatening inborn error of sulfur metabolism. Analysis of hepatic glutathione (GSH) metabolism in a mouse model of HCU demonstrated significant depletion of cysteine, GSH, and GSH disulfide independent of the block in trans-sulfuration compared with wild-type controls. HCU induced the expression of the catalytic and regulatory subunits of γ-glutamyl ligase, GSH synthase (GS), γ-glutamyl transpeptidase 1, 5-oxoprolinase (OPLAH), and the GSH-dependent methylglyoxal detoxification enzyme, glyoxalase-1. Multiple components of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant-response regulatory axis were induced without any detectable activation of Nrf2. Metabolomic analysis revealed the accumulation of multiple γ-glutamyl amino acids and that plasma ophthalmate levels could serve as a noninvasive marker for hepatic redox stress. Neither cysteine, nor betaine treatment was able to reverse the observed enzyme inductions. Taurine treatment normalized the expression levels of γ-glutamyl ligase C/M, GS, OPLAH, and glyoxalase-1, and reversed HCU-induced deficits in protein glutathionylation by acting to double GSH levels relative to controls. Collectively, our data indicate that the perturbation of the γ-glutamyl cycle could contribute to multiple sequelae in HCU and that taurine has significant therapeutic potential for both HCU and other diseases for which GSH depletion is a critical pathogenic factor.-Maclean, K. N., Jiang, H., Aivazidis, S., Kim, E., Shearn, C. T., Harris, P. S., Petersen, D. R., Allen, R. H., Stabler, S. P., Roede, J. R. Taurine treatment prevents derangement of the hepatic γ-glutamyl cycle and methylglyoxal metabolism in a mouse model of classical homocystinuria: regulatory crosstalk between thiol and sulfinic acid metabolism.
胱硫醚β-合酶缺乏型高同型半胱氨酸血症（HCU）是一种尚未完全阐明的、危及生命的先天性硫代谢紊乱。对 HCU 小鼠模型的肝谷胱甘肽（GSH）代谢分析表明，与野生型对照相比，半胱氨酸、GSH 和 GSH 二硫化物的显著耗竭与转硫途径的阻断无关。HCU 诱导了 γ-谷氨酰连接酶、GSH 合成酶（GS）、γ-谷氨酰转肽酶 1、5-氧脯氨酸酶（OPLAH）和 GSH 依赖的甲基乙二醛解毒酶——醛糖还原酶-1 的催化亚基和调节亚基的表达。转录因子核因子（红系衍生 2）样 2（Nrf2）介导的抗氧化反应调控轴的多个组成部分被诱导，但 Nrf2 没有任何可检测的激活。代谢组学分析显示，多种 γ-谷氨酰氨基酸的积累，并且血浆眼氨酸水平可以作为肝氧化还原应激的非侵入性标志物。半胱氨酸或甜菜碱处理均不能逆转观察到的酶诱导。牛磺酸处理使 γ-谷氨酰连接酶 C/M、GS、OPLAH 和醛糖还原酶-1 的表达水平正常化，并通过使 GSH 水平相对于对照增加一倍来逆转 HCU 诱导的蛋白质谷胱甘肽化缺陷。总的来说，我们的数据表明，γ-谷氨酰循环的紊乱可能导致 HCU 的多种后遗症，并且牛磺酸对 HCU 和其他 GSH 耗竭是关键致病因素的疾病具有显著的治疗潜力。-Maclean, K. N., Jiang, H., Aivazidis, S., Kim, E., Shearn, C. T., Harris, P. S., Petersen, D. R., Allen, R. H., Stabler, S. P., Roede, J. R. 牛磺酸治疗可防止经典同型半胱氨酸尿症小鼠模型中肝 γ-谷氨酰循环和甲基乙二醛代谢的紊乱：硫醇和亚磺酸代谢之间的调节交叉对话。
