PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity

Affiliations

• Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
• Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
• Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
• Department of Biology, Stanford University, Stanford, CA, USA.
• Department of Biochemistry, Stanford University, Stanford, CA, USA.
• Department of Chemistry, Stanford University, Stanford, CA, USA.
• Department of Bioengineering, Stanford University, Stanford, CA, USA.
• Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
• Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
• Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
• Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
• Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
• Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
• Arc Institute, Palo Alto, CA, USA.
• Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
• Sarafan ChEM-H, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
• Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
• Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
• Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
• The Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.

PMID: 39112712 DOI: 10.1038/s41586-024-07801-6

Abstract

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

牛磺酸是一种条件性必需微量营养素，也是人体内最丰富的氨基酸之一。在内源性牛磺酸代谢过程中，专门的酶参与了牛磺酸从半胱氨酸的生物合成以及其次级代谢产物的下游代谢。其中一个牛磺酸代谢产物是N-乙酰牛磺酸。N-乙酰牛磺酸的水平受到多种刺激的动态调节，这些刺激会改变牛磺酸或乙酸的流量，包括耐力运动、饮食中的牛磺酸补充和酒精消费。迄今为止，参与N-乙酰牛磺酸代谢的酶的身份以及N-乙酰牛磺酸本身的潜在功能仍未明确。在这项研究中，我们发现与体质指数相关的孤儿酶磷酸三酯酶相关酶（PTER）是一种生理性的N-乙酰牛磺酸水解酶。体外实验表明，PTER催化N-乙酰牛磺酸水解为牛磺酸和乙酸。在小鼠体内，PTER在肾脏、肝脏和脑干中表达。对小鼠进行Pter基因敲除后，体内N-乙酰牛磺酸水解活性完全丧失，N-乙酰牛磺酸水平系统性升高。经过增加牛磺酸水平的刺激后，Pter敲除小鼠表现出减少食物摄入、对饮食诱导的肥胖具有抵抗力以及改善的葡萄糖稳态。向肥胖的野生型小鼠体内施用N-乙酰牛磺酸也能以GFRAL依赖的方式减少食物摄入和体重。这些数据将PTER置于次级牛磺酸代谢的中心酶节点，并揭示了PTER和N-乙酰牛磺酸在体重控制和能量平衡中的作用。

References 

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