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Title: The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats

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. But, 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. In order 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 also 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 themore » 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.« less
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [3] ;  [3] ;  [4] ;  [5] ;  [1] ;  [1]
  1. National Center for Research in Energy and Materials, Sao Paulo (Brazil). National Lab. of Biosciences
  2. National Center for Research in Energy and Materials, Sao Paulo (Brazil). National Lab. of Biosciences; Univ. of Oxford (United Kingdom). Structural Genomics Consortium
  3. National Center for Research in Energy and Materials, Sao Paulo (Brazil). National Lab. of Nanotechnologies
  4. Univ. of Oxford (United Kingdom). Structural Genomics Consortium
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource
Publication Date:
Grant/Contract Number:
AC02-76SF00515; 2014/20673–2; 2015/25832–4; 2014/19518–2; 2014/12663–7; 2014/17820–3; 2013/05668–0
Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 292; Journal Issue: 27; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; cancer; glutaminase; human; metabolism; x-ray crystallography; isoform
OSTI Identifier:
1374373