A newly discovered role for the enzyme glutamine synthetase could have important implications for developing anticancer drugs according to a new UCL study.

An intrinsic part of tumor growth is the sprouting of blood vessels, which supply cancerous tumors with the blood and energy that they need to survive.

An international group of scientists led by Professor Peter Carmeliet at VIB in Belgium, together with Professor Francesco Luigi Gervasio (UCL Chemistry and UCL Institute of Structural Molecular Biology), noticed an unusual connection between the enzyme glutamine synthetase, which was not previously known to be involved in regulating vascular development, and the growth of new blood vessels.

Glutamine synthetase is known to catalyze the condensation of glutamate and ammonia to form glutamine and thus it plays an essential role in the nitrogen metabolism.

The research, published in Nature and primarily funded by the EPSRC and the EU, could lead to the development of drugs that could restrict the growth of tumors by inhibiting the way in which the enzyme behaves.

The team—including researchers at the American Cancer Society, Sun Yat-Sen University, and the National Natural Science Foundation of China—used a combination of computational and experimental techniques.

These revealed that the enzymes were “moonlighting” as facilitators for vascular sprouting, fixing a fatty acid to their surface, which then helps the enzyme move to the cell membrane where the vascular developmental activity takes place.

The simulations at UCL predicted the binding mode of the fatty acid, and mutagenesis experiments on cells later confirmed the computational predictions.

The discovery of this behavior indicates that by mutating the enzyme this vascular sprouting could be prevented completely.

Professor Gervasio said: “It was very exciting to see that the details of the ‘secret’ activity of glutamine synthetase predicted by simulations were spot on and can be used to design new anticancer drugs.”

In comparison with other anticancer drugs, the new drug target could be used in combination with other methods to shut down the blood supply to solid tumors. The new application may be more suitable than other therapies that restrict blood vessel growth that use other enzymes like kinase as their target, as these suffer from the emergence of drug resistance.

The anticancer properties of this therapy could be used without stopping other useful functions in the body as typically the largest formation of new vessels occurs in tumors.

“One of the most important considerations in drug discovery is to find well-characterized targets with a significant role in the disease. Therefore, the first and crucial step is to understand the role of the enzyme in the disease,” added Professor Gervasio.