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. Author manuscript; available in PMC: 2013 Sep 19.
Published in final edited form as: Hematol Oncol Clin North Am. 2012 Jun;26(3):629–ix. doi: 10.1016/j.hoc.2012.02.002

Figure 4.

Figure 4

The impact of dihydrofolate reductase inhibitors on folate pools within cells. The left panel illustrates that under physiological conditions dihydrofolate (DHF) produced during the synthesis of thymidylate mediated by thymidylate synthase is reduced to tetrahydrofolate (THF) so rapidly due to the high levels of dihydrofolate reductase (DHFR) within cells that the DHF level is trivial compared to the level of tetrahydrofolate. The right panel illustrates the impact of suppression of DHFR by several 4-amino antifolates. High levels of DHF build up in cells by continued thymidylate synthase activity, interconversion of THF cofactors to 5,10-methyleneTHF and oxidation to DHF. This leads to depletion of THF cofactor levels within cells and cessation of THF cofactor-dependent reactions. High DHF levels compete with MTX for the small percentage of enzyme sufficient to maintain THF cofactor pools within cells.