Dihydrofolate reductase
From Proteopedia
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| + | [[Image:DHFR_reaction.gif|frame|The reaction catalyzed by DHFR reduces a double bond in DHF to form THF by transfering a hydride from NADPH]] | ||
The enzyme [[dihydrofolate reductase]] (DHFR) occurs in all organisms and has been particularly well-studied in the bacterium Escherichia coli and in humans<ref>DOI:10.1146/annurev.biophys.33.110502.133613</ref><ref>https://en.wikipedia.org/wiki/Dihydrofolate_reductase</ref><ref>https://pdb101.rcsb.org/motm/34</ref>. 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<ref>doi:10.3390/molecules24061140</ref>, 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. | The enzyme [[dihydrofolate reductase]] (DHFR) occurs in all organisms and has been particularly well-studied in the bacterium Escherichia coli and in humans<ref>DOI:10.1146/annurev.biophys.33.110502.133613</ref><ref>https://en.wikipedia.org/wiki/Dihydrofolate_reductase</ref><ref>https://pdb101.rcsb.org/motm/34</ref>. 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<ref>doi:10.3390/molecules24061140</ref>, 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. | ||
| - | == DHFR | + | |
| + | == DHFR occurs in all organisms and most cells== | ||
[[Image:34-DihydrofolateReductase-3dfr-1dls.PNG|thumb|350px|E. coli (left) and human (right) DHFR have a similar architecture and mode of binding to NADPH(green) and the competitive inhibitor methotrexate(purple). Original image by David Goodsell]] | [[Image:34-DihydrofolateReductase-3dfr-1dls.PNG|thumb|350px|E. coli (left) and human (right) DHFR have a similar architecture and mode of binding to NADPH(green) and the competitive inhibitor methotrexate(purple). Original image by David Goodsell]] | ||
Revision as of 19:54, 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 occurs in all organisms and most cells
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
Proteopedia Page Contributors and Editors (what is this?)
Michal Harel, Karsten Theis, Alexander Berchansky, Joel L. Sussman, Tzvia Selzer, Jaime Prilusky, Eric Martz, Eran Hodis, David Canner
