Cancer is a leading cause of death in the world, especially in developedcountries. These last years, metabolism has emerged as an hallmark ofcancer. Indeed the metabolic reprogramming is a key feature of cancer cellswhich allows them to produce the necessary metabolites to their growth.Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step of theserine pathway. This reaction diverts the glycolytic 3-phosphoglycerate toform phosphohydroxypyruvate. The reaction product is then metabolized byphosphoserine aminotransferase-1 and phosphoserine phosphatase togenerate serine.Two recent studies have shown that PHGDH is overexpressed in a subsetof melanoma and breast cancer. It has been shown that depleting PHGDHstrongly inhibited the proliferation of cancer cells where PHGDH isoverexpressed making this enzyme an interesting therapeutic target. Thisyear, new PHGDH inhibitors were reported in three independentpublications showing the growing interest in serine pathway.The aim of my project is to have a better understanding of the catalytic andinhibition mechanisms of PHGDH at the molecular level. Crystallography isthe method of choice to achieve this objective. It will be combined withenzymatic characterizations and mutagenesis to help formation of gooddiffracting crystals. Computational modelisation of the enzyme will give afirst overview a full length PHGDH. Finally, screening of an in-housechemical library will be carried out to discover new fragments binding onPHGDH, which could lead to new anticancer compounds.
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