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Localization of Human Glutamate Dehydrogenases Provides Insights into Their Metabolic Role and Their Involvement in Disease Processes

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Abstract

Glutamate dehydrogenase (GDH) catalyzes the reversible deamination of l-glutamate to α-ketoglutarate and ammonia. In mammals, GDH contributes to important processes such as amino acid and carbohydrate metabolism, energy production, ammonia management, neurotransmitter recycling and insulin secretion. In humans, two isoforms of GDH are found, namely hGDH1 and hGDH2, with the former being ubiquitously expressed and the latter found mainly in brain, testis and kidney. These two iso-enzymes display highly divergent allosteric properties, especially concerning their basal activity, ADP activation and GTP inhibition. On the other hand, both enzymes are thought to predominantly localize in the mitochondrial matrix, even though alternative localizations have been proposed. To further study the subcellular localization of the two human iso-enzymes, we created HEK293 cell lines stably over-expressing hGDH1 and hGDH2. In these cell lines, immunofluorescence and enzymatic analyses verified the overexpression of both hGDH1 and hGDH2 iso-enzymes, whereas subcellular fractionation followed by immunoblotting showed their predominantly mitochondrial localization. Given that previous studies have only indirectly compared the subcellular localization of the two iso-enzymes, we co-expressed them tagged with different fluorescent dyes (green and red fluorescent protein for hGDH1 and hGDH2, respectively) and found them to co-localize. Despite the wealth of information related to the functional properties of hGDH1 and hGDH2 and the availability of the hGDH1 structure, there is still an ongoing debate concerning their metabolic role and their involvement in disease processes. Data on the localization of hGDHs, as the ones presented here, could contribute to better understanding of the function of these important human enzymes.

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Acknowledgements

This work would not have been completed without the valuable assistance of Dr. Christina Dimovasili. We would also like to thank Dr. Dimitra Kotzamani and Dr. Maria Savaki for their help with confocal microscopy, Cynthia Manassaki for coordinating the overall project and Rena Skoula for her continuous aid with technical issues. Finally, we cordially acknowledge the vision and inspiration to work in this exciting field of research provided to us by Professor Andreas Plaitakis.

Funding

This work has been supported by intramural grants of the University of Crete, Heraklion, Crete, Greece, through the Special Account for Research - Research Funding Programs: (1) “Structural studies on human glutamate dehydrogenase iso-enzymes” (Grant Code: KA4374), (2) “Knock-out of GLUD1 and GLUD2 genes from human cell lines, using the CRISPR/Cas9 system” (Grant Code: KA4435).

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  1. Neurology Laboratory, Medical School, University of Crete, Heraklion, Crete, Greece

    Lambros Mathioudakis, Mara Bourbouli, Elisavet Daklada, Sofia Kargatzi, Kleita Michaelidou & Ioannis Zaganas

  2. Department of Neurology, University Hospital of Heraklion, Heraklion, Crete, Greece

    Ioannis Zaganas

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  1. Lambros Mathioudakis
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Correspondence to Ioannis Zaganas.

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Mathioudakis, L., Bourbouli, M., Daklada, E. et al. Localization of Human Glutamate Dehydrogenases Provides Insights into Their Metabolic Role and Their Involvement in Disease Processes. Neurochem Res 44, 170–187 (2019). https://doi.org/10.1007/s11064-018-2575-y

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