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)