Litso, I.; Plaitakis, A.; Fadouloglou, V.E.; Providaki, M.; Kokkinidis, M.; Zaganas, I. Structural Evolution of Primate Glutamate Dehydrogenase 2 as Revealed by In Silico Predictions and Experimentally Determined Structures. Biomolecules 2023, 14, 22, doi:10.3390/biom14010022.
Litso, I.; Plaitakis, A.; Fadouloglou, V.E.; Providaki, M.; Kokkinidis, M.; Zaganas, I. Structural Evolution of Primate Glutamate Dehydrogenase 2 as Revealed by In Silico Predictions and Experimentally Determined Structures. Biomolecules 2023, 14, 22, doi:10.3390/biom14010022.
Litso, I.; Plaitakis, A.; Fadouloglou, V.E.; Providaki, M.; Kokkinidis, M.; Zaganas, I. Structural Evolution of Primate Glutamate Dehydrogenase 2 as Revealed by In Silico Predictions and Experimentally Determined Structures. Biomolecules 2023, 14, 22, doi:10.3390/biom14010022.
Litso, I.; Plaitakis, A.; Fadouloglou, V.E.; Providaki, M.; Kokkinidis, M.; Zaganas, I. Structural Evolution of Primate Glutamate Dehydrogenase 2 as Revealed by In Silico Predictions and Experimentally Determined Structures. Biomolecules 2023, 14, 22, doi:10.3390/biom14010022.
Abstract
Glutamate dehydrogenase (GDH) interconverts glutamate to a-ketoglutarate and ammonia, interconnecting amino acid and carbohydrate metabolism. In humans, two functional GDH genes, GLUD1 and GLUD2, encode for hGDH1 and hGDH2, respectively. GLUD2 evolved from retro-transponsition of the GLUD1 gene in the common ancestor of modern apes. These two isoenzymes are involved in the pathophysiology of neoplastic, neurodegenerative, and metabolic disorders. The 3D structures of hGDH1 and hGDH2 have been experimentally determined; however, no information is available about the path of GDH2 structure changes during primate evolution. Here, we compare the structures predicted by the AlphaFold Colab method for the GDH2 enzyme of modern apes and their extinct primate ancestors. Also, we analyze the individual effect of amino acid substitutions emerging during primate evolution. Our most important finding is that the predicted structure of GDH2 in the common ancestor of apes was the steppingstone for the structural evolution of primate GDH2s. Two changes with a strong functional impact occurring at the first evolutionary step, Arg443Ser and Gly456Ala, had a destabilizing and stabilizing effect, respectively, making this step the most important one. Subsequently, GDH2 underwent additional modifications that fine-tuned its enzymatic properties to adapt to the functional needs of modern-day primate tissues.
Keywords
glutamate dehydrogenase; alpha fold; protein structure prediction; primate evolution
Subject
Biology and Life Sciences, Ecology, Evolution, Behavior and Systematics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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