Metabolite sensing and signaling in cell metabolism

Abstract

Metabolite sensing is one of the most fundamental biological processes. During evolution, multilayered mechanisms developed to sense fluctuations in a wide spectrum of metabolites, including nutrients, to coordinate cellular metabolism and biological networks. To date, AMPK and mTOR signaling are among the best-understood metabolite-sensing and signaling pathways. Here, we propose a sensor-transducer-effector model to describe known mechanisms of metabolite sensing and signaling. We define a metabolite sensor by its specificity, dynamicity, and functionality. We group the actions of metabolite sensing into three different modes: metabolite sensor-mediated signaling, metabolite-sensing module, and sensing by conjugating. With these modes of action, we provide a systematic view of how cells sense sugars, lipids, amino acids, and metabolic intermediates. In the future perspective, we suggest a systematic screen of metabolite-sensing macromolecules, high-throughput discovery of biomacromolecule-metabolite interactomes, and functional metabolomics to advance our knowledge of metabolite sensing and signaling. Most importantly, targeting metabolite sensing holds great promise in therapeutic intervention of metabolic diseases and in improving healthy aging.

Metabolite Regulatory Interactions Control Plant Respiratory Metabolism via Target of Rapamycin (TOR) Kinase Activation

“…Metabolite concentrations are a crucial aspect of the posttranslational control of respiration in all organisms by acting as substrates, allosteric effectors, and feedback inhibitors of various metabolic enzymes (Plaxton and Podestá, 2006). Likewise, many metabolites induce signal transduction cascades that link nutritional or environmental status to changes in enzyme expression levels and posttranslational modifications (Wang and Lei, 2018). In plants, the best understood examples of nutrient signaling metabolites are carbohydrates.…”

Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells

“…Accumulating evidence suggests that intermediate metabolites are critical players in the crosstalk between metabolism and gene expression for stem-cell fate decision 2,42,43 . For example, two well-studied intermediates in the tricarboxylic acid (TCA) cycle, α-ketoglutarate, and Flavin adenine dinucleotide, function as cofactors of histone and DNA demethylases to epigenetically modulate global transcription for stemcell maintenance 4,15,44 . In NPCs, however, glycolysis is the major source of energy, producing a plethora of intermediate metabolites, whose roles as signalling molecules in gene regulation and NPC homeostasis are poorly understood.…”

“…What controls the functional switch of metabolic enzymes is still largely unknown. One means of switching may involve feedback or feedforward control of their enzymatic activities by post-translational modifications with intermediate metabolites 15,16 . For example, methylglyoxal, an intermediate metabolite produced from G3P during glycolysis modifies GAPDH in a non-enzymatic manner, leading to inhibition of its enzymatic activities 17 .…”

Electrochemical Immuno- and Aptamer-Based Assays for Bacteria: Pros and Cons over Traditional Detection Schemes

“…Standing separately are metabolic sensors based on the detection of signals associated with specific reactions related to bacterial metabolism [ 100 , 101 ] ( Figure 1 ). Those approaches may be very efficient but generally are either low specific or based on very individual metabolic biomarkers of specific bacterial species, and thus they do not form general analytical platforms.…”