Dihydrofolate reductase

From Proteopedia

Revision as of 22:30, 6 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]. 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, 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.

Sources

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

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 and humans 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^[2]. Mice and rats lack the second gene but also show DHFR activity in mitochondria^[3].

Reactions catalyzed

Dihydrofolate reductase (DHFR, 1.5.1.3 [2]) is an enzyme which uses the co-factor NADPH as electron donor which converts it to NADP. It catalyzes the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). 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.^[4]. Some bacterial enzymes also accept folic acid as a substrate ^[5] 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)^[6]. Both enzymes participate in the biosynthesis of pyrimidine.^[7]

See also

• Molecular Playground/DHFR
  
• Malarial Dihydrofolate Reductase as Drug Target.
  

Relevance

Antifolate inhibitors like Methotrexate (MTX) which is very similar to folic acid are used in cancer therapy.

3D Structures of Dihydrofolate reductase

Dihydrofolate reductase 3D structures

Additional Resources

• For additional information, see: Cancer.
• See also Molecular Playground/DHFR.

References