Skip to content
MS
Sign in
unreviewed

Dihydrofolate reductase (DHFR)

3 reactions · 3 pathways

Cofactors used

NADP+ · B3 (Niacin) NADPH · B3 (Niacin) THF (folate) · B9 (Folate)

Clinical / pharmacological. Target of methotrexate, trimethoprim, pyrimethamine

What it does, reaction by reaction

3 reactions

One-Carbon Metabolism (Folate Cycle) Amino Acid & Nitrogen Metabolism · Cytosol + mitochondrion

step 1 Irreversible

Dihydrofolate (DHF) + NADPH + H⁺ → tetrahydrofolate (THF) + NADP⁺

Converts Dihydrofolate (DHF) NADPH H+ into Tetrahydrofolate (THF) NADP+

› Notes

Dihydrofolate reductase (DHFR) regenerates reduced THF after DHF is produced by thymidylate synthase. NADPH is required; this is an essential, effectively irreversible reductive regeneration step and the pharmacologic target of methotrexate, trimethoprim, and pyrimethamine.

Deoxyribonucleotide Formation (Ribonucleotide Reductase pathway and thymidylate synthesis) Nucleotide Metabolism · Cytosol

step 7 Irreversible/directional

DHF → THF

Converts Dihydrofolate (DHF) into Tetrahydrofolate (THF)

› Notes

DHFR catalyzes DHF + NADPH + H+ → THF + NADP+. This reaction regenerates reduced folate after every thymidylate synthase turnover and is essential to maintain dTMP synthesis.

Pyrimidine De Novo Synthesis (through to UMP, then CTP/dTMP) Nucleotide Metabolism · Cytosol (one mitochondrial step)

step 14 Irreversible/directional

DHF → THF; THF → 5,10-methylene-THF

Converts Dihydrofolate (DHF) into Tetrahydrofolate (THF)

› Notes

Dihydrofolate reductase (DHFR) regenerates THF: DHF + NADPH + H+ → THF + NADP+. Serine hydroxymethyltransferase then catalyzes THF + serine ⇌ 5,10-methylene-THF + glycine, using pyridoxal phosphate; this restores the one-carbon donor required by thymidylate synthase.

Showing all 3 reactions.

What accelerates and inhibits it

Regulation is pathway-specific, so each context is listed separately

1 entries

Deoxyribonucleotide Formation (Ribonucleotide Reductase pathway and thymidylate synthesis)

Listed there as: Dihydrofolate reductase

Accelerated by

DHF and NADPH availability

Inhibited by

Methotrexate, trimethoprim (much greater selectivity for microbial DHFR), pemetrexed

Hormonal control

Proliferation-associated transcriptional induction; no canonical acute hormonal allosteric regulator.

Recent literature

Refresh

Europe PMC · fetched just now · sorted by publication date

  1. 1
    Phthalazine as a medically versatile polyheterocyclic core with underexplored anticancer potential.

    Biegański M, Matysiak J, Szeliga M. · 2026-09-18

    open access unreviewed
  2. 2
    HSV-1 metabolic hijacking: Mechanisms to precision therapeutics.

    Kuang S, Zhang J, Chen J, He Z, Yang J, Li S, Ding J, Ma Z, Zhang B. · 2026-08-11

    open access unreviewed
  3. 3
    Experimental and computational analysis of glycan processing at increased monoclonal antibody productivities.

    Pranomphon R, Gialamoidou S, Yamabhai M, Sharfstein ST, Jiménez Del Val I. · 2026-07-20

    open access unreviewed
  4. 4
    Live-attenuated <i>Toxoplasma gondii</i> RHΔ<i>ddx6</i> mutant establishes comprehensive immunity against acute, chronic, and congenital toxoplasmosis.

    Yang Z, Wang J, Wu J, Fan Y, Ying T, Zhang H, Bai J, Wang Y, Liu P, Li G, Nie M, Tian X, Mei X, Zhang Z, Wang… · 2026-08-07

    open access unreviewed
  5. 5
    Comprehensive safety assessment of novel dicholine folate vitamin.

    Jonaitis T, Ulmann M, Wiesler G, Lukasik KV. · 2026-07-15

    open access unreviewed
  6. 6
    Inflammation and carcinogenesis: molecular targets and small-molecule intervention strategies.

    Lu WJ, Ojha R, Rana M, Gautam V, Li JY, Wang SA. · 2026-06-26

    open access unreviewed
  7. 7
    Design, synthesis, and antibacterial activity study of pyrroloquinazoline diamine derivatives.

    Cheng M, Tian Y, Shang J, He W, Zheng Y, Yan C, Chen X, Li J, Jiang Y, Fu Q, Deng X, Xiao X, Song M. · 2026-06-24

    open access unreviewed
  8. 8
    MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming.

    Kisielewska M, Suwała S, Drąg-Zalesińska M, Rembiałkowska N. · 2026-06-15

    open access unreviewed
  9. 9
    Integration of nuclear mechanosensing with integrin-extracellular matrix adhesions.

    Sandria S, King MC. · 2026-05-28

    cited 1× open access unreviewed
  10. 10
    Comment on "sharp rise in high-virulence <i>Bordetella pertussis</i> with macrolides resistance in Northern China".

    Li Z, Li Z, Ma X. · 2026-04-27

    open access unreviewed

External claims. These come from an index outside this database and are not checked against it. Treat them as leads.