Folylpoly-g-glutamate Synthetase and g-Glutamyl Hydrolase: Two important enzymes in folate metabolism Goal: Increased knowledge of folate use and control in biological pathways in order to increase the potency and decrease the toxicity of anti-folates in chemotherapy. Folic acid is a key vitamin in human nutrition. Cellular folates contain a reduced pteridine heterocycle and a poly g-glutamyl peptide "tail." Two enzymes, folylpoly-g-glutatmate synthetase (FPGS) and g-glutamyl hydrolase (GH), being studied by our research group, catalyze the biosynthesis and hydrolytic cleavage, respectively, of the polyglutamyl portion of cellular folates and antifolate drugs. Recent research has involved the synthesis of several fluoro- and phosphoamino acids and their incorporation into folates and antifolate drugs. These efforts have led to the synthesis of fluoropeptides or phosphapeptides for biochemical investigation as inhibitors or stimulators of the reactions catalyzed by FPGS or GH. In collaborative research, our new compounds are being used in intact mammalian cells to assess the role of poly-g-glutamate formation and hydrolysis in normal folate-dependent one-carbon biochemistry and also in the pharmacology of antifolate drugs used in the treatment of cancer. Clyde Smith has recently published the crystal structure of L. casei FPGS. Ribbon representation of L. casei FPGS. The N-terminal domain is shown in blue and the C-terminal domain is in red.  The interdomain linker is colored green. The ATP-binding site is indicated by the magenta loop representing the glycine-rich P-loop and the W-loop, the folate binding site, is shown in cyan. Researchers interested in FPGS and GH Andrew Bognar at the University of Toronto. John Galivan at the Wadsworth Center NYDH. John McGuire at the Roswell Park Cancer Institute. Thomas Ryan at the Wadsworth Center NYDH. Barry Shane at Berkeley. Clyde Smith at Auckland University. Richard Moran at the Virginia Commonwealth University If you are a researcher interested in FPGS or GH please drop us a note and we will add you to our list!

 
Last updated: March 2003
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