Stephen posted about Glycine at the end of November 2015 on astrocytomaoptions under Exploring strategies for IDH1 mutated gliomas. I'll just paste it here again. Anyway, does anyone have any experience with this supplement? It is fairly cheap and non-toxic, so was maybe anyone thinking about trying it?
Reversing hypersuccinylation
November 28, 2015A research team at Fudan University, China, published a study [46] in the journal Molecular Cell, demonstrating a novel mechanism for the tumorigenic effects of IDH mutations. In this study, the oncometabolite 2-HG, produced in large quantities by mutant IDH enzymes, was found to competitively inhibit the activity of the citric acid cycle enzyme succinate dehydrogenase (SDH), leading to the buildup of succinate and succinyl-coenzyme A, and the hypersuccinylation of lysine. Lysine is an amino acid component of proteins. IDH1-mutated patient glioma samples were found to have significantly higher levels of succinylated lysine than IDH1 wild-type glioma samples, with the most intense succinylation being localized in mitochondria.
The effects of this mitochondrial hypersuccinylation were then examined. Overexpression of IDH1 R132H mutation in cells led to increased succinylation at succinylation sites in mitochondrial enzymes pyruvate dehydrogenase (PDHA1), succinate dehydrogenase (SDHB) and cytochrome c oxidase. The latter two enzymes are components of the electron transfer chain. Succinylation of these enzymes led to their decreased activity, causing impaired oxidative mitochondrial metabolism. Importantly, IDH1 R132H overexpression induced the accumulation of BCL-2, an anti-apoptotic protein, in the mitochondrial membrane. Reversing hypersuccinylation by genetic manipulations also reversed the apoptosis resistance of the cells.
The researchers then hypothesized that glycine may be able to reverse the hypersuccinylation found in 1DH1 mutant cells, as the condensation of glycine and succinyl-coenzyme A would send the resulting 5-aminolevulinic acid into the heme biosynthesis pathway, leaving fewer succinyl groups available to succinylate proteins. This was indeed found to be the case in vitro. Next, mice were subcutaneously xenografted with HT1080 fibrosarcoma cells, which harbor a naturally-occuring IDH1 R132C mutation. The mice were fed a chow supplemented with 5% glycine. Impressively, tumor weights in the glycine supplemented mice were 67% smaller than the tumors from mice fed the control diet, and succinylation levels were also lower, providing proof of principle of the glycine-supplemented diet.
Note, however, that a glycine concentration of 100 mM was used in vitro, far higher than the ~1 mM that is achievable in serum, even with very high glycine doses. The study did not exclude that tumor growth inhibition may have been primarily due to anti-angiogenic effects, as seen in melanoma mouse studies.
Glycine is an amino acid and neurotransmitter. A summary of the use of glycine as a dietary supplement is found at the website examine.com.
Hi Matjaz,
ReplyDeleteI realise this is an older post but I recently read that gliomas maybe able to metabolize methionine and that glycine competes with methionine for absorption I’m the human diet. Therefore, supplementing with it can decrease methionine absorption. However, glycine also helps to create glutamate which IDH mutant gliomas (and wild type) use as an energy source. So, I’d guess you have to use this supplement very carefully.
Maria
Glutamate can be created from glutamine through the action of glutaminase. Is that what you meant?
DeleteNo, I’ve read the glycine helps to facilitate the process of making glutamate (or glutamine). I didn’t bookmark it, so I’ll try to find it. I didn’t scrutinize it very much...just a passing read.
DeleteMaria
https://www.ncbi.nlm.nih.gov/m/pubmed/17962467/
DeleteGlycine is one of the building blocks of glutathione. I'm unfamiliar with the role of glycine in glutamine/glutamate synthesis. Plenty of glutamine and glutamate is consumed directly in food, so I'm not sure how much would need to be synthesized beyond what is consumed in the diet.
DeleteAs far as diet goes, trying to lower levels of circulating glutamate or glutamine probably will not have much of an effect on the levels of glutamate in the brain because glutamate is a vital neurotransmitter and homeostasis will ensure there is always enough glutamate in the brain environment. Glutamate deficiency in the brain would be a serious problem. Targeting specific enzymes overexpressed in tumors such as glutamate dehydrogenases would likely be a more viable strategy. A clinically approved and reasonably safe GLUD2 inhibitor could be a very useful tool, although I don't know of any such thing existing at this point in time.
Thanks, Stephen. I appreciate it.
DeleteYes, I guess I know that lower dietary gluthione probably will not have an impact but maybe it’s for peace of mind.
I’m looking in cannibis to help inhibit glutamate. We talked about this briefly a while ago and you shared one study. I suppose it’s a shot in the dark...but...
Did you read about GLS1 and 2 in my p53 loss post? MYC facilitates one and P53 the other. Since I have a p53 loss and no MYC mutation, maybe those with inhibit glutamate in the cells?
Maria
Tumors like yours almost never do have MYC mutations, but MYC gets upregulated in other ways. For example ~20% of IDH1 mutant lower grade gliomas that have progressed to high grade will have MYC amplification (many copies of the MYC gene rather than just two). MYC can be perfectly active and upregulated even in the absence of a mutation.
DeleteGlutaminases (GLS1 and GLS2) do not metabolize glutathione as you mentioned in your post, but deaminate glutamine to glutamate.
Other transcription factors besides p53 can regulate GLS2 transcription. More importantly, glutaminases are probably not nearly as important as the glutamate dehydrogenases (especially GLUD2) in the economy of IDH1 mutant cells. There is plenty of ready-made glutamate in the brain environment to supply IDH1 mutant cells with a substrate for 2-hydroxyglutarate production, so the need to make glutamate from glutamine via glutaminase is not that critical. Consequently glutamate dehydrogenase is likely a better therapeutic target than glutaminase in IDH1 mutant cells.
Hi Stephen,
ReplyDeleteThank you.
Is there a GLUD2 or glutamate dehydrogenase therapy?
Maria
Not that I'm aware of. Chloroquine has been proposed as a glutamate dehydrogenase inhibitor, but it is far more specific for GLUD1 and is pretty weak even as a GLUD1 inhibitor.
Delete