Dihydrofolate reductase
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== Reactions catalyzed == | == Reactions catalyzed == | ||
| - | [[Dihydrofolate reductase]] (DHFR, 1.5.1.3 [https://enzyme.expasy.org/EC/1.5.1.3]) is an enzyme which uses the co-factor NADPH as electron donor. It catalyzes the reduction of <scene name='82/82636/Substrate_product/1'>dihydrofolic acid (DHF) to tetrahydrofolic acid (THF)</scene> as NADPH is oxidized to NADP+. The mammalian enzymes also accept folic acid as a substrate, reducing it to THF. This allows the use of folic acid, which is easier to synthesize than DHF or THF, to fortify food.<ref>DOI:10.3746/pnf.2014.19.4.247</ref>. Some bacterial enzymes also accept folic acid as a substrate <ref>DOI:10.1021/acs.biochem.6b01268</ref> but it acts as a competitive inhibitor in the E. coli enzyme. | + | [[Dihydrofolate reductase]] (DHFR, 1.5.1.3 [https://enzyme.expasy.org/EC/1.5.1.3]) is an enzyme which uses the co-factor NADPH as electron donor. It catalyzes the reduction of <scene name='82/82636/Substrate_product/1'>dihydrofolic acid (DHF) to tetrahydrofolic acid (THF)</scene> as NADPH is oxidized to NADP+. The mammalian enzymes also accept folic acid as a substrate, reducing it to THF. This allows the use of folic acid, which is easier to synthesize than DHF or THF, to fortify food.<ref>DOI:10.3746/pnf.2014.19.4.247</ref><ref>https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/</ref>. Some bacterial enzymes also accept folic acid as a substrate <ref>DOI:10.1021/acs.biochem.6b01268</ref> but it acts as a competitive inhibitor in the E. coli enzyme. |
Revision as of 17:02, 7 January 2022
The enzyme dihydrofolate reductase (DHFR) occurs in all organisms and has been particularly well-studied in the bacterium Escherichia coli and in humans[1][2][3]. It catalyzes the reduction of dihydrofolate to tetrahydrofolate, with NADPH acting as hydride donor. The human enzyme is a target for developing inhibitors used in anti-cancer chemotherapies[4], while the bacterial enzymes are targets for developing inhibitors as antibiotics. DHFR is a model enzyme for studying the kinetics, mechanism, and inhibition of enzymatic reactions and the underlying structure and conformational dynamics.
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DHFR from different organisms
DHFR is found in all organisms. Some bacteria acquire resistance to DHFR inhibitors through expressing a second form of DHFR coded on a plasmid. The enzymes from E. coli (ecDHFR) and humans (hDHFR) have similar folds, while the plasmid-encoded enzyme has an unrelated fold. In humans, DHFR is expressed in most tissues[1], and there are two genes, DHFR and DHFR2/DHFRL1, the latter targeted to mitochondria[5]. Mice and rats lack the second gene but also show DHFR activity in mitochondria[6].
Reactions catalyzed
Dihydrofolate reductase (DHFR, 1.5.1.3 [2]) is an enzyme which uses the co-factor NADPH as electron donor. It catalyzes the reduction of as NADPH is oxidized to NADP+. The mammalian enzymes also accept folic acid as a substrate, reducing it to THF. This allows the use of folic acid, which is easier to synthesize than DHF or THF, to fortify food.[7][8]. Some bacterial enzymes also accept folic acid as a substrate [9] but it acts as a competitive inhibitor in the E. coli enzyme.
The folate is a form of the essential vitamin B9. Folate is not part of our natural diet (it contains dihydrofolate and tetrahydrofolate, sometimes as a poly-glutamate conjugate) but is bioavailable and simpler to synthesize.
Relevance
DHFR forms a complex with thymidylate synthase (TS)[10]. Both enzymes participate in the biosynthesis of pyrimidine.[11]
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See also
3D Structures of Dihydrofolate reductase
Dihydrofolate reductase 3D structures
Additional Resources
- For additional information, see: Cancer.
- See also Molecular Playground/DHFR.
References
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