Abstract 1234 PTER controls energy balance via bidirectional taurine N-acetylation/hydrolysis

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream metabolism of taurine into taurine-containing metabolites. One such downstream taurine metabolite is N-acetyltaurine, an amidated conjugate of taurine and acetate. While taurine N-acetyltransferase activity has been previously detected in mammalian cells, the molecular identity of this enzyme, and its potential physiologic relevance, have remained unknown. Here we show that the body mass index-associated orphan enzyme PTER (phosphotriesterase-related) is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER selectively catalyzes N-acetyltaurine biosynthesis from taurine and acetate, as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of taurine N-acetyltransferase/hydrolysis activities and concomitant >2-10-fold elevation of N-acetyltaurine levels across tissues. Upon dietary or physiologic stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight and reduced adiposity. These phenotypes can also be recapitulated by pharmacological administration of N-acetyltaurine to wild-type mice. Together, these data define a PTER-dependent pathway of taurine metabolism linked to energy balance. Our studies uncover enzymatic regulation of a previously enigmatic pathway of taurine metabolism. We also provide a unifying biochemical mechanism to explain the genetic association between PTER and body mass index. Lastly, this PTER-dependent taurine pathway highlights an under-appreciated role for taurine metabolites in the physiologic effects of taurine. This work was supported by the US National Institutes of Health (DK105203 and DK124265 to J.Z.L.), the Wu Tsai Human Performance Alliance (research grant to J.Z.L.) and the Stanford Diabetes Research Center (P30DK116074 to J.Z.L.).