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PDBsum entry 5uqe
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References listed in PDB file
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Key reference
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Title
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The origin and evolution of human glutaminases and their atypical c-Terminal ankyrin repeats.
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Authors
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C.C.Pasquali,
Z.Islam,
D.Adamoski,
I.M.Ferreira,
R.D.Righeto,
J.Bettini,
R.V.Portugal,
W.W.Yue,
A.Gonzalez,
S.M.G.Dias,
A.L.B.Ambrosio.
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Ref.
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J Biol Chem, 2017,
292,
11572-11585.
[DOI no: ]
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PubMed id
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Abstract
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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.
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