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Connection 4 BH4 Depletion and eNOS Uncoupling Beyond Homocysteine Beyond its homocysteine-mediated BH4 oxidation effect, MTHFR impairment reduces BH4 recycling through a second mechanism: the dihydrobiopterin reductase (DHFR) enzyme that regenerates BH4 from BH2 requires dihydrofolate reductase activity an enzyme that uses NADPH to reduce both dihydrofolate to THF and BH2 to BH4