A PTER-dependent pathway of taurine metabolism linked to energy balance

Wei Wei; Xuchao Lyu; Andrew L Markhard; Sipei Fu; Rachel E Mardjuki; Peter E Cavanagh; Xianfeng Zeng; Jakub Rajniak; Nannan Lu; Shuke Xiao; Meng Zhao; Maria Dolores Moya-Garzon; Steven D Truong; Jonathan Chiu-Chun Chou; Lianna W Wat; Saranya Chidambaranathan-Reghupaty; Laetitia Coassolo; Duo Xu; Fangfang Shen; Wentao Huang; Cuauhtemoc B Ramirez; Cholsoon Jang; Katrin J Svensson; Michael A Fischbach; Jonathan Z Long

doi:10.1101/2024.03.21.586194

A PTER-dependent pathway of taurine metabolism linked to energy balance

bioRxiv [Preprint]. 2024 Mar 22:2024.03.21.586194. doi: 10.1101/2024.03.21.586194.

Authors

Wei Wei^{1

2}, Xuchao Lyu^{1

2

3}, Andrew L Markhard^{1

2}, Sipei Fu^{1

2

4}, Rachel E Mardjuki^{2

5

6}, Peter E Cavanagh⁵, Xianfeng Zeng^{2

7}, Jakub Rajniak^{2

7}, Nannan Lu^{8

9}, Shuke Xiao^{1

2}, Meng Zhao^{1

10

11}, Maria Dolores Moya-Garzon^{1

2

3}, Steven D Truong^{1

2}, Jonathan Chiu-Chun Chou⁶, Lianna W Wat^{1

10

12}, Saranya Chidambaranathan-Reghupaty^{1

10

12}, Laetitia Coassolo^{1

10

12}, Duo Xu^{2

5}, Fangfang Shen^{2

6}, Wentao Huang¹¹, Cuauhtemoc B Ramirez¹³, Cholsoon Jang¹³, Katrin J Svensson^{1

10

12}, Michael A Fischbach^{2

7}, Jonathan Z Long^{1

2

3

10

12

14}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
³ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁴ Department of Biology, Stanford University, Stanford, CA, USA.
⁵ Department of Biochemistry, Stanford University, Stanford, CA, USA.
⁶ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁷ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁸ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
⁹ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
¹⁴ The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.

Abstract

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans^1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites^4,5. One such taurine metabolite is N-acetyltaurine⁶. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise⁷, nutritional taurine supplementation⁸, and alcohol consumption^6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells^6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)¹⁰ is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

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