Dr. Eyal Arbely from the Department of Chemistry and the National Institute for Biotechnology in the Negev (NIBN) has been awarded a prestigious European Research Council (ERC) Starting Grant. He will receive €1.5 million over the next five years for a project entitled ‘AcetyLys’ which aims to develop synthetic biology-based methods for understanding the regulation of glucose metabolism in cancerous and non-cancerous cells.
Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. “As synthetic biologists, we apply principles of engineering to biological systems", says Arbely. "While the traditional approach of biological sciences is to understand biological systems by studying their building blocks, the basic approach of synthetic biology is to manipulate, combine and redesign these building blocks with the aim to construct (synthesize) new biological systems for basic research and beneficial biotechnological applications." In particular, Arbely is studying biologically relevant questions by developing and applying methods for manipulating the genetic code.
The genetic code is the Rosetta stone that translates the DNA sequence into amino acids that make proteins. Except for a few exceptions, the genetic code is common to practically all known organisms. "In principal, this means that almost all known organisms share the same vocabulary that is composed of 20 words – the 20 common amino acids. We expand the genetic code by adding a new—non-natural— amino acid, and thus introduce new "words" to this Rosetta stone. Hence, our modified cells have a vocabulary of more than 20 amino acids. The ability to introduce new amino acids with new chemical groups into proteins, allows us to produce proteins with improved or novel properties that can help in solving biologically important question."
Arbely proposed to develop and apply such synthetic biology-based tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Healthy and cancerous cells can regulate the activity of enzymes by modulating the addition and removal of a small chemical modification called acetyl group. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is a key regulator of cellular metabolism in general and in glycolysis in particular.
The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, the Arbely group will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, they will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. They will also decipher the mechanism by which acetylation is regulated by 18 deacetylases. The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.