The de novo purine synthesis pathway is part of the larger one-carbon (1C) metabolic pathway that utilizes tetrahydrofolate (THF) as the universal one carbon donor and acceptor. The 1C pathway has been shown to be upregulated in cancer cells to satisfy the need for various metabolites, including purines for DNA synthesis and replication. Folate analogues, i.e., antifolates, have been developed as cancer therapeutics by targeting folate utilizing enzymes in this pathway. A series of molecules has been developed collaboratively that mimic the scaffold of THF and inhibit folate utilizing de novo purine synthesis enzymes: β-glycinamide ribonucleotide formyltransferase (GARFTase) and aminoimidazole-4-carboxymide ribonucleotide formyltransferase (AICARFTase). Both folates and antifolates are subjected to modification upon cell entry by the enzyme folylpolyglutamate synthetase (FPGS), an enzyme that consecutively adds multiple additional glutamates to the mono-glutamyl moiety of folates and antifolates. There are multiple knowledge gaps surrounding FPGS, primarily owing to a lack of robust methods to express, purify, and analyze human FPGS. In this poster, I will discuss expression and purification strategies for human FPGS along with the development of activity assays for FPGS. Additionally, current data on characterizing the modification of potent GARFTase and AICARFTase inhibitors by FPGS will be discussed. These data define the determinants of antifolate inhibitors required for modification by FPGS, which has implications in cancer drug resistance.

Understanding cellular modification of <i>de novo</i> purine synthesis inhibitors: Impact of folylpolyglutamate synthetase (FPGS) on the action of cancer therapeutics

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Understanding cellular modification of de novo purine synthesis inhibitors: Impact of folylpolyglutamate synthetase (FPGS) on the action of cancer therapeutics