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Dipeptide Tyr-Asp inhibits glyceraldehyde 3-phosphate dehydrogenase activity, affecting redox metabolism and boosting plant stress resistance.

ABSTRACT: Proteogenic dipeptides are not only intermediates of proteolysis but also an emerging class of small molecule regulators, with diverse and specific functions. We have recently reported a novel in vitro interaction between the dipeptide Tyr-Asp and the Arabidopsis glycolytic enzyme glyceraldehyde 3- phosphate dehydrogenase (GAPDH). To understand the functional significance of Tyr-Asp/GAPDH binding, we examined the effect produced on the enzymatic activity. Results demonstrate that low to mid micro-molar concentrations of Tyr-Asp, but none of the other tested dipeptides, inhibit GAPDH activity both in vitro and in planta. Inhibition of the GAPDH activity was associated with a shift of the flux from glycolysis towards the pentose phosphate pathway and an increase in the NADPH/NADP+ ratio, a known response to cope with oxidative stress. In addition to GAPDH, the Tyr-Asp protein interactome comprised further stress-related proteins, including multiple chaperones. In line with the molecular data, Tyr-Asp supplementation improved growth performance of both Arabidopsis and tobacco seedlings subjected to oxidative stress conditions. By contrast, no such improvement was measured, neither for the free amino acids nor the other tested dipeptides, demonstrating that the action of Tyr-Asp is specific and independent of the degradation of Tyr-Asp to the constituent amino acids. Finally, inhibition of Arabidopsis phosphoenolpyruvate carboxykinase activity reveals a multisite regulation of glycolytic/gluconeogenic flux by dipeptides. In summary, our data suggest proteogenic dipeptides as a novel class of small-molecule regulators operating at the nexus of stress, protein degradation and metabolism.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Arabidopsis Thaliana (mouse-ear Cress)

TISSUE(S): Rosette

SUBMITTER: Michal Gorka

LAB HEAD: Aleksandra Skirzcy

PROVIDER: PXD019332 | Pride | 2021-05-10

REPOSITORIES: Pride

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Project description:This is the model with unfitted parameters described in the article Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress Markus Ralser, Mirjam M Wamelink, Axel Kowald, Birgit Gerisch, Gino Heeren, Eduard A Struys, Edda Klipp, Cornelis Jakobs, Michael Breitenbach, Hans Lehrach and Sylvia Krobitsch, J Biol 2007 6(4):10; PMID: 18154684 , doi: 10.1186/jbiol61 Abstract: BACKGROUND: Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role. RESULTS: We recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide. Here we show that this phenotype is conserved in Caenorhabditis elegans and that the underlying mechanism is based on a redirection of the metabolic flux from glycolysis to the pentose phosphate pathway, altering the redox equilibrium of the cytoplasmic NADP(H) pool. Remarkably, another key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known to be inactivated in response to various oxidant treatments, and we show that this provokes a similar redirection of the metabolic flux. CONCLUSION: The naturally occurring inactivation of GAPDH functions as a metabolic switch for rerouting the carbohydrate flux to counteract oxidative stress. As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions. Different realtive enzyme velocities can be simulated by varying the parameters k_rel_TPI and k_rel_GAPDH . This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team. For more information see the terms of use . To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

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Dipeptide Tyr-Asp inhibits glyceraldehyde 3-phosphate dehydrogenase activity, affecting redox metabolism and boosting plant stress resistance.

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