HEALTH NEWS

Study Title:

Green Tea Polyphenols and Protein Metabolism

Study Abstract

Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and, in animals, is extensively regulated by a number of metabolites. Gain of function mutations in GDH that abrogate GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS), resulting in increased pancreatic β-cells responsiveness to leucine and susceptibility to hypoglycemia following high protein meals. We have previously shown that two of the polyphenols from green tea (EGCG and ECG) inhibit GDH in-vitro and that EGCG blocks GDH-mediated insulin secretion in wild type rat islets. Using structural and site-directed mutagenesis studies, we demonstrate that ECG binds to the same site as the allosteric regulator, ADP. Perifusion assays using pancreatic islets from transgenic mice expressing a human HHS form of GDH demonstrate that the hyper-response to glutamine caused by dysregulated GDH is blocked by the addition of EGCG. As observed in HHS patients, these transgenic mice are hypersensitive to amino acid feeding and this is abrogated by oral administration of EGCG prior to challenge. Finally, the low basal blood glucose level in the HHS mouse model is improved upon chronic administration of EGCG. These results suggest that this common natural product, or some derivative thereof, may prove useful in controlling this genetic disorder. Of broader clinical implication is that other groups have shown restriction of glutamine catabolism via these GDH inhibitors can be useful in treating various tumors. This HHS transgenic mouse model offers a highly useful means to test these agents in-vivo.

From press release:

A compound found in green tea shows great promise for the development of drugs to treat two types of tumors and a deadly congenital disease. The discovery is the result of research led by principal investigator, Dr. Thomas Smith at The Donald Danforth Plant Science Center and his colleagues at The Children's Hospital of Philadelphia.

Their findings were recently published in The Journal of Biological Chemistry.

Glutamate dehydrogenase (GDH) is found in all living organisms and is responsible for the digestion of amino acids. In animals, GDH is controlled by a complex network of metabolites. For decades it was not clear why animals required such regulation but other kingdoms did not. This was partially answered by the Stanley group's finding that a deadly congenital disease, hyperinsulinism/hyperammonemia (HHS), is caused by the loss of some of this regulation. In this disorder, patients (typically children) respond to the consumption of protein by over secreting insulin, becoming severely hypoglycemic, often leading to death.

Using atomic structures to understand the differences between animals and plants, Dr. Smith and his colleagues discovered that two compounds found naturally in green tea are able to compensate for this genetic disorder by turning off GDH in isolated and when the green tea compounds were administered orally. The Smith lab also used X-ray crystallography to determine the atomic structure of these green tea compounds bound to the enzyme. With this atomic information, they hope to be able to modify these natural compounds to design and develop better drugs.

Interestingly, two other research groups have validated and extended these findings to demonstrate that blocking GDH with green tea is very effective at killing two different kinds of tumors; glioblastomas, an aggressive type of brain tumor, and tuberous sclerosis complex disorder, a genetic disease that causes non-malignant tumors to grow on a number of organs.

"While these compounds from green tea are extremely safe and consumed by millions every day, they have a number of properties that make them difficult to use as actual drugs. Nevertheless, our ongoing collaboration with the Stanley lab shows that there are natural compounds from plants that can control this deadly disorder and, with the atomic structure in hand, can be used as a starting point for further drug design."

Study Information

C. Li, M. Li, P. Chen, S. Narayan, F. M. Matschinsky, M. J. Bennett, C. Stanley, T. J. Smith
Green Tea Polyphenols Control Dysregulated Glutamate Dehydrogenase In Transgenic Mice By Hijacking The ADP Activation Site
Journal of Biological Chemistry
2011 August
The Donald Danforth Plant Science Center at The Children's Hospital of Philadelphia.