Abstract
On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. However, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont. We propose an evolutionary model wherein the appearance of the most active enzyme isoform, glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class. The ankyrin (ANK) repeats in the glutaminases were acquired early in their evolution. To obtain information on ANK folding, we solved two high-resolution structures of the ANK repeat-containing C termini of both kidney-type glutaminase (KGA) and GLS2 isoforms (glutaminase B and liver-type glutaminase). We found that the glutaminase ANK repeats form unique intramolecular contacts through two highly conserved motifs; curiously, this arrangement occludes a region usually involved in ANK-mediated protein-protein interactions. We also solved the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins' compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. Collectively, these results provide information about glutaminases that may aid in the design of isoform-specific glutaminase inhibitors.
Highlights
On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals
We propose an evolutionary model wherein the appearance of the most active enzyme isoform, glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class
This apparent redundancy in glutaminase isoforms can be explained by differential tissue expression patterns, as well as the cell proliferation state
Summary
On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. The multidomain architecture of human glutaminases glutaminase C (GAC), are generated by alternative splicing of the GLS gene (2q32.2) Both isoforms are activated by inorganic phosphate and inhibited by glutamate (16 –18). By identifying homologous prokaryotic and eukaryotic sequences and building a phylogenetic tree, we propose that the multidomain architecture of the mammalian glutaminases GLS and GLS2 is a feature inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont From this phylogenetic tree, we propose an evolutionary model wherein a GLS-like predecessor gene in tunicates gave rise to the currently known human isozymes through exon remodeling, gene duplication, and retrotransposition events. Increase the chances of successfully inhibiting the enzyme in a clinical setting
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