Sunday, 24 January 2016

Glycine?

Hello all,

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, 2015
A 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.

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