Browse by author
Lookup NU author(s): Professor Wyatt YueORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021. Cancer cells exhibit an altered metabolic phenotype, consuming higher levels of the amino acid glutamine. This metabolic reprogramming depends on increased mitochondrial glutaminase activity to convert glutamine to glutamate, an essential precursor for bioenergetic and biosynthetic processes in cells. Mammals encode the kidney-type (GLS) and liver-type (GLS2) glutaminase isozymes. GLS is overexpressed in cancer and associated with enhanced malignancy. On the other hand, GLS2 is either a tumor suppressor or an oncogene, depending on the tumor type. The GLS structure and activation mechanism are well known, while the structural determinants for GLS2 activation remain elusive. Here, we describe the structure of the human glutaminase domain of GLS2, followed by the functional characterization of the residues critical for its activity. Increasing concentrations of GLS2 lead to tetramer stabilization, a process enhanced by phosphate. In GLS2, the so-called “lid loop” is in a rigid open conformation, which may be related to its higher affinity for phosphate and lower affinity for glutamine; hence, it has lower glutaminase activity than GLS. The lower affinity of GLS2 for glutamine is also related to its less electropositive catalytic site than GLS, as indicated by a Thr225Lys substitution within the catalytic site decreasing the GLS2 glutamine concentration corresponding to half-maximal velocity (K0.5). Finally, we show that the Lys253Ala substitution (corresponding to the Lys320Ala in the GLS “activation” loop, formerly known as the “gating” loop) renders a highly active protein in stable tetrameric form. We conclude that the “activation” loop, a known target for GLS inhibition, may also be a drug target for GLS2.
Author(s): Ferreira IM, Quesnay JEN, Bastos AC, Rodrigues CT, Vollmar M, Krojer T, Strain-Damerell C, Burgess-Brown NA, von Delft F, Yue WW, Dias SM, Ambrosio AL
Publication type: Article
Publication status: Published
Journal: Biochimie
Year: 2021
Volume: 185
Pages: 96-104
Print publication date: 01/06/2021
Online publication date: 18/03/2021
Acceptance date: 14/03/2021
Date deposited: 12/09/2024
ISSN (print): 0300-9084
ISSN (electronic): 6183-1638
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.biochi.2021.03.009
DOI: 10.1016/j.biochi.2021.03.009
PubMed id: 33746066
Altmetrics provided by Altmetric
