Inhibition of mammalian thymidylate synthase by 10-formyltetrahydropteroylpolyglutamate.

Abstract

Reduced derivatives of 10-formylfolate have been evaluated as inhibitors of mammalian thymidylate synthase (EC 2.1.1.45) from H35 hepatoma cells. With 5,10-methylenetetrahydrofolylheptaglutamate as the substrate, 10-formyltetrahydrofolylmonoglutamate is a competitive inhibitor with a Ki of 2.4 microM, which is reduced to 0.1 microM for the heptaglutamate derivative. 10-Formyldihydrofolylmono- and -heptaglutamate are approximately threefold less inhibitory than the tetrahydro analog. The concentrations of 10-formyltetrahydrofolate and 10-formyldihydrofolate were measured in dividing hepatoma cells by a novel enzymatic assay and were found to be 5 microM and undetectable, respectively. These results suggest that the concentration of 10-formyltetrahydrofolate within the dividing cells has the potential to severely inhibit or modulate thymidylate biosynthesis.

• Authors: M Balinska, M Rhee, J M Whiteley, D G Priest, J Galivan
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 284 Issue 1 Pg. 219-22 (Jan 1991) ISSN: 0003-9861 [Print] United States
• PMID: 1989499 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Formyltetrahydrofolates
• Glutamates
• 10-formyltetrahydropteroylglutamic acid
• Thymidylate Synthase
• Leucovorin

Topics

• Animals
• Binding, Competitive
• Formyltetrahydrofolates (pharmacology)
• Glutamates (pharmacology)
• In Vitro Techniques
• Kinetics
• Leucovorin (analogs & derivatives, metabolism)
• Liver Neoplasms, Experimental (enzymology)
• Thymidylate Synthase (antagonists & inhibitors)
• Tumor Cells, Cultured