Evolutionary Changes in Primate Glutamate Dehydrogenases 1 and 2 Influence the Protein Regulation by Ligands, Targeting and Posttranslational Modifications

Abstract

There are two paralogs of glutamate dehydrogenase (GDH) in humans encoded by the GLUD1 and GLUD2 genes as a result of a recent retroposition during the evolution of primates. The two human GDHs possess significantly different regulation by allosteric ligands, which is not fully characterized at the structural level. Recent advances in identification of the GDH ligand binding sites provide a deeper perspective on the significance of the accumulated substitutions within the two GDH paralogs. In this review, we describe the evolution of GLUD1 and GLUD2 after the duplication event in primates using the accumulated sequencing and structural data. A new gibbon GLUD2 sequence questions the indispensability of ancestral R496S and G509A mutations for GLUD2 irresponsiveness to GTP, providing an alternative with potentially similar regulatory features. The data of both GLUD1 and GLUD2 evolution not only confirm substitutions enhancing GLUD2 mitochondrial targeting, but also reveal a conserved mutation in ape GLUD1 mitochondrial targeting sequence that likely reduces its transport to mitochondria. Moreover, the information of GDH interactors, posttranslational modification and subcellular localization are provided for better understanding of the GDH mutations. Medically significant point mutations causing deregulation of GDH are considered from the structural and regulatory point of view.

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition

“…Six of these seven amino acid changes are present in every member of the hominoid radiation that possesses the GLUD2 gene (Figure 1). An exception is the Hylobates moloch genus of the gibbon family, in which the Arg443Ser and Gly456Ala changes were reversed in association with the appearance of four new mutations [33]. These observations have raised questions regarding the positive selection of these sites during the GLUD2 evolution, and the role of these residues in the functional adaptation of GDH2 [33].…”

“…An exception is the Hylobates moloch genus of the gibbon family, in which the Arg443Ser and Gly456Ala changes were reversed in association with the appearance of four new mutations [33]. These observations have raised questions regarding the positive selection of these sites during the GLUD2 evolution, and the role of these residues in the functional adaptation of GDH2 [33]. Concerning the latter, it is presently unclear whether the four new amino acid replacements that emerged along with this reversal in Hylobates moloch provide to the gibbon GDH2 properties similar to those conferred by the Arg443Ser and Gly456Ala replacements to human GDH2 [33].…”

“…These observations have raised questions regarding the positive selection of these sites during the GLUD2 evolution, and the role of these residues in the functional adaptation of GDH2 [33]. Concerning the latter, it is presently unclear whether the four new amino acid replacements that emerged along with this reversal in Hylobates moloch provide to the gibbon GDH2 properties similar to those conferred by the Arg443Ser and Gly456Ala replacements to human GDH2 [33]. Moreover, particularly intriguing is the absence of gibbon GLUD1 sequences in UniProt [33], raising the theoretical possibility (according to Aleshina and Aleshin) that GLUD1 might have become a pseudogene after the emergence of GLUD2 in the gibbon.…”

“…Concerning the latter, it is presently unclear whether the four new amino acid replacements that emerged along with this reversal in Hylobates moloch provide to the gibbon GDH2 properties similar to those conferred by the Arg443Ser and Gly456Ala replacements to human GDH2 [33]. Moreover, particularly intriguing is the absence of gibbon GLUD1 sequences in UniProt [33], raising the theoretical possibility (according to Aleshina and Aleshin) that GLUD1 might have become a pseudogene after the emergence of GLUD2 in the gibbon. While this seems unlikely, reversal of the Arg443Ser and Gly457Ala mutations reinstates ancestral amino acids present in hGDH1 that contribute to the housekeeping properties of the enzyme.…”

“…As such, whether this reversal permitted the gibbon GDH2 to take over some of the metabolic duties of hGDH1 and whether this has affected the GLUD1 evolution remain to be further explored. Additional studies, including the functional characterization of gibbon GDH2s, are needed to better understand not only the evolutionary trajectory of the GLUD2 gene but also its impact on the biology of these species [33].…”