DHFR and cancer: The physiological relevance of possible FH4 in human DHFR via slow release might be even more pronounced in the acidic microenvironment of cancer where the limited extent of recycling folate metabolites for one-carbon metabolism is expected, as the free form of the mature cofactor FH4 was shown to undergo irreversible oxidative decay to pterins (without formation of FH2) at a pH below 7 (ref. 64) and also reducing agents was reported to no longer prevent oxidative degradation of FH4 at acidic pH61.