![]() Crystal structures of representative family members of the different types of PHGDH. Two forms of the type III enzyme exist depending on whether lysine (type K) or histidine (type H) is present at the active site (left). Additional amino acids at the N-terminus are not explicitly shown as variations in length and composition of this part of the protein depend on the species. (B) Basic domain structure found within the three enzyme types of PHGDH shaded by domain. Dephosphorylation of phosphoserine by phosphoserine phosphatase (PSPH) gives rise to L-serine. The subsequent transamination reaction is catalyzed by phosphoserine aminotransferase (PSAT), which uses glutamate (Glu) as nitrogen donor and thereby produces phosphoserine and α-ketoglutarate (αKG). (A) 3-Step synthesis scheme of endogenous L-serine starts with the oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate by PHGDH and simultaneous reduction of the cofactor NAD + to NADH. ![]() ![]() L-Serine synthesis pathway and basic domain structure of PHGDH In vitro enzyme activity measurements show that the catalytic subunit of PHGDH is still active and that PHGDH activity could be significantly inhibited with adenosine 5’-diphosphoribose. We also report the crystal structure of the catalytic subunit of human PHGDH, a dimer, solved with bound cofactor in one monomer and both cofactor and L-tartrate in the second monomer. We have investigated substrate analogues to assess whether PHGDH might possess other enzymatic roles that could explain its occasional over-expression in cancer, as well as to help with the design of specific inhibitors. ![]() PHGDH catalyzes the NAD +-dependent conversion of 3-phosphoglycerate to phosphohydroxypyruvate, which is the first step in the de novo synthesis pathway of serine, a critical amino acid for protein and nucleic acid biosynthesis. Here we focus on the characterization of human 3-phosphoglycerate dehydrogenase (PHGDH). To efficiently target these enzymes, a good understanding of their enzymatic function and structure, as well as knowledge regarding any substrate or catalytic promiscuity is required. Although primary roles for many metabolic proteins have been identified, some are promiscuous in regards to the reaction they catalyze. Cancer cells reprogram their metabolism and energy production to sustain increased growth, enable metastasis and overcome resistance to cancer treatments. ![]()
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