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Glutamine



Let’s talk about diseases. Have you ever heard of Huntington disease? The disease named after physician George Hungtington is a neurogenerative disorder, which is genetically programmed. There is one gene, called huntingtin, and this encodes for a polymeric stretch of glutamines (polyQ). Different people have different length. If a person has 35 or below Q, this is safe, and a person shouldn’t be concerned with this. But when the stretch is 36 Q or more, a person shall be aware, that at some point in life, this disease may start to progress. The more Q are in the stretch, the earlier the symptoms will develop.

The actual function of hungtingtin in the cells is still unknown, but the malfunction has been described much better. Longer polyQ stretches are more likely to clump at some point during the lifetime. This statistical process will progress until it will accumulate in amyloids and inclusion bodies, and there will be more and more of these, until neurons will be unable to cope with the cargo, and die as the result. It then makes a great challenge for modern chemistry to develop a treatment of this cruel and deadly disorder.

Other than in proteins, the consumption of glutamine is also enormously elevated in cancer cell metabolism. This brings a hope, that by suppressing some glutamine metabolic pathways, a cancer inhibition would also be possible.

Interesting readings:

- DeBerardinis, R. J. and Cheng, T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 29, 2010, 313-324, doi: 10.1038/onc.2009.358
- Wise, D. R. and Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci., 35, 2010, 427-433, doi: 10.1016/j.tibs.2010.05.003

Two nice reviews on the role of glutamate metabolism in cancer, and possible entries for therapeutics development.

- Kar, K. et al. Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependent. Nat. Struct. Mol. Biol., 18, 2011, 328-336, doi: 10.1038/nsmb.1992

A model study on the nucleation mechanism in polyQ aggregation.

- Wetzel, R. Physical Chemistry of Polyglutamine: Intriguing Tales of a Monotonous Sequence. J. Mol. Biol., 421, 2012, 466-490, doi: 10.1016/j.jmb.2012.01.030

A nice review on polyQ.