Biology subjects

Markhard, A. L.

Publications and source records attributed to Markhard, A. L..

3 recordsLinked to original sources

bioRxiv2026

Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway

Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1-3. Using untargeted metabolomics, here we show that circulating levels of the metabolite para-tyramine-O-sulfate (pTOS) are increased >1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulfation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.

physiology↗

bioRxiv2024

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

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 biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. 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 consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, 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.

biochemistry↗

bioRxiv2019

Molecular basis of EMRE-dependence of the human mitochondrial calcium uniporter

The mitochondrial uniporter is calcium-activated calcium channel complex critical for cellular signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan-specific, single-pass transmembrane protein EMRE for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of the human MCUs dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent D. discoideum MCU (DdMCU) and H. sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in DdMCU that can be transplanted to HsMCU to render it EMRE-dependent. We call this region in human MCU the EMRE-dependence domain (EDD). Crosslinking experiments show that HsEMRE directly interacts with MCU at both of its transmembrane domains as well as the EDD. Based on previously published structures of fungal MCU homologs, the EDD segment is located distal to the calcium pores selectivity filter and appears flexible. We propose that EMRE stabilizes EDD of MCU, permitting both channel opening and calcium conductance

biochemistry↗