The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism
Open accessAbstract
Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls , known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a “gating loop” as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion.
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Cites
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Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation
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Self-citation
Cited by
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
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Role of Mitochondria in Ferroptosis
Gao, M., Yi, J., Zhu, J., Minikes, A. M., Monian, P., Thompson, C. B., & Jiang, X. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.10.042 · Cited by 2,120
From Krebs to clinic: glutamine metabolism to cancer therapy
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Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer
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The development of the concept of ferroptosis
Hirschhorn, T., & Stockwell, B. R. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.043 · Cited by 1,052
Metadata
- Authors
- Cassago, A., Ferreira, A. P. S., Ferreira, I. M., Fornezari, C., Gomes, E. R. M., Greene, K. S., Pereira, H. M., Garratt, R. C., Dias, S. M. G., & Ambrosio, A. L. B.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-01-06
- Volume
- 109
- Issue
- 4
- Pages
- 1092-1097
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2126116618
- Cited by
- 285
- References
- 35
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
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- Cassago, A., Ferreira, A. P. S., Ferreira, I. M., Fornezari, C., Gomes, E. R. M., Greene, K. S., Pereira, H. M., Garratt, R. C., Dias, S. M. G., & Ambrosio, A. L. B. (2012). Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1112495109
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