Elusive structure of metabolic enzyme solved by MBI’s Low Boon Chuan and Jayaraman Sivaraman of Department of Biological Sciences
Associate Professor Low Boon Chuan, in collaboration with Associate Professor Jayaraman Sivaraman, have solved the X-ray structure of glutaminase, a key metabolic enzyme involved in cancer metabolism, bound to the chemical inhibitor BPTES. Low and Sivaraman’s paper, Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism, is published in PNAS.
“We now provide the first detailed structure of how BPTES inhibits glutaminase by inducing a dramatic allosteric shift… These findings could offer a new cancer treatment regime that is more potent but less cytotoxic”, says Associate Prof Low Boon Chuan. “Intriguingly, this enzyme can be activated by epidermal growth factor acting through a well known growth promoting Ras-Erk signaling pathway.”
“…These findings could offer a new cancer treatment regime that is more potent but less cytotoxic, says Associate Prof Low Boon Chuan.„
The Glutaminase Story
Glutaminase is required to break down the amino acid glutamine in a process termed glutaminolysis. This process provides a cell with energy and as such is exploited by cancer cells to meet their growing energy demands. Feeding off the breakdown of glutamine, cancer cells are able to grow and divide into a tumour. Glutaminase therefore makes a promising therapeutic target for the prevention of tumour progression. Inhibition of this enzyme could effectively starve the cancer cells of their energy source.
Glutaminase can be inhibited by the small molecule BPTES, currently part of a preclinical trial in the USA. Low and colleagues used X-ray crystallography to elucidate the structure of glutaminase when bound to its inhibitor BPTES, highlighting the previously unknown conformational changes that occur when BPTES binds glutaminase. These novel findings on how and where BPTES binds glutaminase provides information vital to the development of improved versions of this inhibitor that will be more effective and have fewer side effects.
Low and colleagues delved further into the glutaminase story through analysis of how this enzyme is triggered into action. Their results showed that the growth factor EGF (epidermal growth factor) induces glutaminase activity , by stimulating the well characterised Ras-Raf-Mek2-Erk kinase pathway.
Hope for Better Therapies?
Armed with structural insights into glutaminase-BPTES binding and the signaling pathway thats activates glutaminase, Low and colleagues sought to determine whether a combination of drugs would be even more effective in at inhibiting glutaminase activity. Results showed that using an inhibitor of Mek2, a component of the pathway that activates glutaminase, in combination with BPTES, resulted in a greater drop in glutaminase activity and cell division. This raises the hope of a new dual-drug cancer treatment regime that is more potent in its effects but less toxic overall.
What Does the Future Hold?
These illuminating findings provide the first detailed descriptions of precisely how BPTES inhibits glutaminase. Moreover, results from this study tie glutaminase activity to that of the Ras-Raf-Mek2-Erk kinase pathway. Taken together these novel insights hold great promise for the development of multi-drug treatments for glutamine-addicted cancers. Low and Sivaraman continue to further this field through the development and analysis of more inhibitors targeting glutaminase.