ISMB Commentary: An unexpected role for the enzyme Glutamine Synthetase

October 2018

Prof Francesco Gervasio’s group has contributed to the discovery and clarification of an unexpected, yet fundamental, role of the enzyme glutamine synthetase.

Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine.  GS is expressed in endothelial cells, fundamentally regulating vascular development. However, a group of scientists led by Prof Peter Carmeliet at VIB in Belgium together with Prof Francesco L. Gervasio found that it surprisingly shows little glutamine synthetizing activity in these cells. Instead, GS localizes in membranes due to an expected (and so-far, unknown) auto-palmitoylation activity. This moonlighting activity turns out to be fundamental for vessel sprouting. However, it was unclear how it happens and which residues are involved. The state-of-the art models and simulations by Prof. Gervasio’s group were able to solve the mystery, showing how palmitoyl-COA binds to the active site (see figure, left) and reacts with cysteine 209 to form a covalent bond. Site-directed mutagenesis of Cys209 later confirmed the computational prediction and validated the proposed mode of action. This new finding, published by Nature at the beginning of September, has important implications for anti-cancer drug discovery, as it might lead to new drugs blocking the vascular development in solid cancers.


Role of glutamine synthetase in angiogenesis beyond glutamine synthesis
Eelen, G.,…, Gervasio, F.L.,…, Carmeliet, P.
Nature (2018) 561, 63-69