N-acetyltaurine is a metabolite whose levels fluctuate with diet and exercise and that undergoes hydrolysis to form taurine and acetate. However, the enzymes that facilitate this reaction were not known. In an effort to address this, Wei et al. used liquid chromatography–mass spectrometry-based activity guided analysis of mouse tissues, detecting high N-acetyltaurine hydrolysis activity in kidney and liver tissues, with reduced N-acetyltaurine levels and a corresponding increase in taurine. Fractionation of kidney cytosol fractions combined with size exclusion chromatography identified a peak of activity. Proteomic analysis revealed a series of candidates with exogenous expression of phosphotriesterase-related (PTER), an orphan metal-dependent hydrolase, sufficient to increase N-acetyltaurine hydrolytic activity in cells. Pter-deficient mice confirmed the loss of hydrolysis activity with targeted metabolomic analysis of N-acetylated amino acids showing only alterations in N-acetyltaurine levels with minimal changes in other N-acetyl amino acids. Previous work has shown a connection between PTER polymorphisms and early onset obesity, so the team examined Pter-deficient mice on a high-fat diet while supplemented with taurine or exposed to treadmill running. In both cases, the mice exhibited lower body weight and food intake with improved glucose homeostasis, suggesting a complex interplay between increased N-acetyltaurine, diet and exercise. The beneficial metabolic effects were attributed to the brainstem, where PTER was expressed and is known to regulate food intake. The addition of an antibody against a candidate brainstem regulator, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), blocked the effects of exogenous N-acetyltaurine. Although there remain open questions about the metabolic regulation between the brainstem and peripheral tissues and the identity of the enzymes required for N-acetyltaurine, the findings from Wei et al. offer the first step to understanding the metabolic and functional roles of N-acetyltaurine.

Original reference: Nature 633, 182–188 (2024)

N-乙酰牛磺酸是一种代谢物，其水平随饮食和运动而波动，并经过水解形成牛磺酸和乙酸盐。然而，促进该反应的酶尚不清楚。为了解决这个问题，Wei 等人。使用基于液相色谱-质谱法的活性引导分析小鼠组织，检测肾脏和肝脏组织中的高N-乙酰牛磺酸水解活性， N-乙酰牛磺酸水平降低，牛磺酸相应增加。肾细胞溶质级分的分级分离与尺寸排阻色谱法相结合，确定了活性峰。蛋白质组学分析揭示了一系列具有磷酸三酯酶相关 (PTER) 外源表达的候选物，PTER 是一种孤儿金属依赖性水解酶，足以增加细胞中的N-乙酰牛磺酸水解活性。 Pter缺陷小鼠通过N-乙酰化氨基酸的靶向代谢组学分析证实了水解活性的丧失，显示仅N-乙酰牛磺酸水平发生变化，而其他N-乙酰氨基酸的变化最小。之前的工作已经表明PTER多态性与早发性肥胖之间存在联系，因此研究小组检查了PTER缺陷小鼠的高脂肪饮食，同时补充牛磺酸或在跑步机上跑步。在这两种情况下，小鼠均表现出较低的体重和食物摄入量，并且葡萄糖稳态得到改善，这表明N-乙酰牛磺酸增加、饮食和运动之间存在复杂的相互作用。有益的代谢作用归因于脑干，PTER 在脑干中表达，并且已知可以调节食物摄入量。 添加针对候选脑干调节剂——神经胶质细胞源性神经营养因子受体α样（GFRAL）的抗体，可以阻断外源性N-乙酰牛磺酸的作用。尽管关于脑干和周围组织之间的代谢调节以及N-乙酰牛磺酸所需酶的身份仍然存在悬而未决的问题，但 Wei 等人的研究结果。为了解N-乙酰牛磺酸的代谢和功能作用迈出了第一步。

原始参考文献： Nature 633 , 182–188 (2024)