D-Glyceraldehyde-3-Phosphate Dehydrogenase Structure and Function

White, Michael R. H.; Garcin, Elsa D.

doi:10.1007/978-3-319-46503-6_15

Cited by 55 publications

(50 citation statements)

References 217 publications

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“…In crocodilians, GAPDH has been studied in the muscle of caiman (226). GAPDH has been shown to be regulated via some posttranslational modifications (224,227,228) and was recently identified as a deimination candidate by our group in cancer (61), as well as in whales (75) and to form part of deiminated protein EV cargo in naked mole rat plasma (79). Deimination of GAPDH may contribute to its multifaceted physiological functions, and the identification of its deimination in several taxa with unusual metabolism and cancer resistance is of considerable interest.…”

Section: Discussionmentioning

confidence: 99%

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

et al. 2020

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Alligators are crocodilians and among few species that endured the Cretaceous-Paleogene extinction event. With long life spans, low metabolic rates, unusual immunological characteristics, including strong antibacterial and antiviral ability, and cancer resistance, crocodilians may hold information for molecular pathways underlying such physiological traits. Peptidylarginine deiminases (PADs) are a group of calcium-activated enzymes that cause posttranslational protein deimination/citrullination in a range of target proteins contributing to protein moonlighting functions in health and disease. PADs are phylogenetically conserved and are also a key regulator of extracellular vesicle (EV) release, a critical part of cellular communication. As little is known about PAD-mediated mechanisms in reptile immunology, this study was aimed at profiling EVs and protein deimination in Alligator mississippiensis. Alligator plasma EVs were found to be polydispersed in a 50-400-nm size range. Key immune, metabolic, and gene regulatory proteins were identified to be posttranslationally deiminated in plasma and plasma EVs, with some overlapping hits, while some were unique to either plasma or plasma EVs. In whole plasma, 112 target proteins were identified to be deiminated, while 77 proteins were found as deiminated protein hits in plasma EVs, whereof 31 were specific for EVs only, including proteins specific for gene regulatory functions (e.g., histones). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed KEGG pathways specific to deiminated proteins in whole plasma related to adipocytokine signaling, while KEGG pathways of deiminated proteins specific to EVs included ribosome, biosynthesis of amino acids, and glycolysis/gluconeogenesis pathways as well as core histones. This highlights roles for EV-mediated export of deiminated protein cargo with roles in metabolism and gene regulation, also related to cancer. The identification of posttranslational deimination and EV-mediated communication Criscitiello et al. Deimination and EV Signatures in Alligator in alligator plasma revealed here contributes to current understanding of protein moonlighting functions and EV-mediated communication in these ancient reptiles, providing novel insight into their unusual immune systems and physiological traits. In addition, our findings may shed light on pathways underlying cancer resistance, antibacterial and antiviral resistance, with translatable value to human pathologies.

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Section: Discussionmentioning

confidence: 99%

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

et al. 2020

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“…1.2.1.12) is a highly conserved glycolytic enzyme in all kingdoms of life. Several non-glycolytic functions of GAPDH have also been observed, classifying this enzyme as prototypical example for moonlighting (for reviews see [ 2 – 6 ]:). In A. thaliana , GapC1 (At3g04120) and GapC2 (At1g13440) are the GAPDH isoforms residing in the cytosol.…”

Section: Introductionmentioning

confidence: 99%

Cytosolic GAPDH as a redox-dependent regulator of energy metabolism

et al. 2018

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BackgroundPlant cytosolic NAD-dependent glyceraldehyde-3-phosphate dehydrogenase (GapC) displays redox-dependent changes in its subcellular localizations and activity. Apart from its fundamental role in glycolysis, it also exhibits moonlighting properties. Since the exceptional redox-sensitivity of GapC has been suggested to play a crucial role in its various functions, we here studied its redox-dependent subcellular localization and the influence of the redox-state on GapC protein interactions.ResultsIn mesophyll protoplasts from Arabidopsis thaliana, colocalization of GapC with mitochondria was more pronounced under reducing conditions than upon oxidative stress. In accordance, reduced GapC showed an increased affinity to the mitochondrial voltage-dependent anion-selective channel (VDAC) compared to the oxidized one. On the other hand, nuclear localization of GapC was increased under oxidizing conditions. The essential role of the catalytic cysteine for nuclear translocation was shown by using the corresponding cysteine mutants. Furthermore, interaction of GapC with the thioredoxin Trx-h3 as a candidate to revert the redox-modifications, occurred in the nucleus of oxidized protoplasts. In a yeast complementation assay, we could demonstrate that the plant-specific non-phosphorylating glyceraldehyde 3-P dehydrogenase (GapN) can substitute for glucose 6-P dehydrogenase to generate NADPH for re-reduction of the Trx system and ROS defense.ConclusionsThe preferred association of reduced, glycolytically active GapC with VDAC suggests a substrate-channeling metabolon at the mitochondrial surface for efficient energy generation. Increased occurrence of oxidized GapC in the nucleus points to a function in signal transduction and gene expression. Furthermore, the interaction of GapC with Trx-h3 in the nucleus indicates reversal of the oxidative cysteine modification after re-establishment of cellular homeostasis. Both, energy metabolism and signal transfer for long-term adjustment and protection from redox-imbalances are mediated by the various functions of GapC. The molecular properties of GapC as a redox-switch are key to its multiple roles in orchestrating energy metabolism.Electronic supplementary materialThe online version of this article (10.1186/s12870-018-1390-6) contains supplementary material, which is available to authorized users.

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“…The key function of GAPDH is attributed to glycolysis, which means that the active tetrameric molecule catalyzes the conversion of glyceraldehyde-3-phosphate to 1,3-bisphospho-d-glycerate [80]. Chemical modifications and denaturation of GAPDH can slow down the glycolytic cycle and disrupt the cellular metabolism [81].…”

Section: Pathologies Associated With Impaired Function Of Gapdhmentioning

confidence: 99%

Glyceraldehyde-3-phosphate Dehydrogenase Is a Multifaceted Therapeutic Target

2020

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme whose role in cell metabolism and homeostasis is well defined, while its function in pathologic processes needs further elucidation. Depending on the cell context, GAPDH may bind a number of physiologically important proteins, control their function and correspondingly affect the cell’s fate. These interprotein interactions and post-translational modifications of GAPDH mediate its cytotoxic or cytoprotective functions in the manner of a Janus-like molecule. In this review, we discuss the functional features of the enzyme in cellular physiology and its possible involvement in human pathologies. In the last part of the article, we describe drugs that can be employed to modulate this enzyme’s function in some pathologic states.

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D-Glyceraldehyde-3-Phosphate Dehydrogenase Structure and Function

Cited by 55 publications

References 217 publications

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

Cytosolic GAPDH as a redox-dependent regulator of energy metabolism

Glyceraldehyde-3-phosphate Dehydrogenase Is a Multifaceted Therapeutic Target

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