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The Odyssey of a Young Gene: Structure–Function Studies in Human Glutamate Dehydrogenases Reveal Evolutionary-Acquired Complex Allosteric Regulation Mechanisms

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Abstract

Mammalian glutamate dehydrogenase (GDH) catalyzes the reversible inter-conversion of glutamate to α-ketoglutarate and ammonia, interconnecting carbon skeleton and nitrogen metabolism. In addition, it functions as an energy switch by its ability to fuel the Krebs cycle depending on the energy status of the cell. As GDH lies at the intersection of several metabolic pathways, its activity is tightly regulated by several allosteric compounds that are metabolic intermediates. In contrast to other mammals that have a single GDH-encoding gene, humans and great apes possess two isoforms of GDH (hGDH1 and hGDH2, encoded by the GLUD1 and GLUD2 genes, respectively) with distinct regulation pattern, but remarkable sequence similarity (they differ, in their mature form, in only 15 of their 505 amino-acids). The GLUD2 gene is considered a very young gene, emerging from the GLUD1 gene through retro-position only recently (<23 million years ago). The new hGDH2 iso-enzyme, through random mutations and natural selection, is thought to have conferred an evolutionary advantage that helped its persistence through primate evolution. The properties of the two highly homologous human GDHs have been studied using purified recombinant hGDH1 and hGDH2 proteins obtained by expression of the corresponding cDNAs in Sf21 cells. According to these studies, in contrast to hGDH1 that maintains basal activity at 35–40 % of its maximal, hGDH2 displays low basal activity that is highly responsive to activation by rising levels of ADP and/or l-leucine which can also act synergistically. While hGDH1 is inhibited potently by GTP, hGDH2 shows remarkable GTP resistance. Furthermore, the two iso-enzymes are differentially inhibited by estrogens, polyamines and neuroleptics, and also differ in heat-lability. To elucidate the molecular mechanisms that underlie these different regulation patterns of the two iso-enzymes (and consequently the evolutionary adaptation of hGDH2 to a new functional role), we have performed mutagenesis at sites of difference in their amino acid sequence. Results showed that the low basal activity, heat-lability and estrogen sensitivity of hGDH2 could be, at least partially, ascribed to the Arg443Ser evolutionary change, whereas resistance to GTP inhibition has been attributed to the Gly456Ala change. Other amino acid substitutions studied thus far cannot explain all the remaining functional differences between the two iso-enzymes. Also, the Arg443Ser/Gly456Ala double mutation in hGDH1 approached the properties of wild-type hGDH2, without being identical to it. The insights into the structural mechanism of enzymatic regulation and the implications in cell biology provided by these findings are discussed.

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Acknowledgments

Most of the research described here has been performed under the guidance of Dr. Andreas Plaitakis, to whom this issue of Neurochemical Research is dedicated to. We (I.V.Z., K.K., V.M., H.L., N.B., G.A. and C.D.) are grateful for his help and inspiration during the last 18 years. This manuscript has been partially co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program: THALIS—UOC, Title “Mitochondrial dysfunction in neurodegenerative diseases” (Grant Code 377226).

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Authors and Affiliations

  1. Neurology Laboratory, Medical School, University of Crete, Voutes, 71003, Heraklion, Crete, Greece

    Ioannis V. Zaganas, Konstantinos Kanavouras, Nikolas Borompokas, Giovanna Arianoglou, Christina Dimovasili, Helen Latsoudis & Vasileios Mastorodemos

  2. Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15310, Ag. Paraskevi, Athens, Greece

    Metaxia Vlassi

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  1. Ioannis V. Zaganas
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  2. Konstantinos Kanavouras
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Correspondence to Ioannis V. Zaganas.

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Zaganas, I.V., Kanavouras, K., Borompokas, N. et al. The Odyssey of a Young Gene: Structure–Function Studies in Human Glutamate Dehydrogenases Reveal Evolutionary-Acquired Complex Allosteric Regulation Mechanisms. Neurochem Res 39, 471–486 (2014). https://doi.org/10.1007/s11064-014-1251-0

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