Dihydrofolate reductase

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Dihydrofolate reductase
Dihydrofolate reductase

Existing structural data: s. UniProt

Properties of human protein
Mass / length primary structure 186 amino acids
Identifier
Gene name DHFR
External IDs
Enzyme classification
EC, category 1.5.1.3 ,  oxidoreductase
Response type reduction
Substrate 7,8-dihydrofolate + NADPH + H +
Products 5,6,7,8-tetrahydrofolate + NADP +
Occurrence
Homology family DHFR
Parent taxon Creature

Dihydrofolate reductase ( DHFR ), also called dihydrofolic acid reductase, are enzymes that hydrogenate folic acid to dihydrofolic acid (DHF) and DHF to tetrahydrofolic acid (THF) . These reactions activate the vitamin folic acid and are essential for nucleotide biosynthesis in all living things. In humans, DHFR occurs in all tissue types. Mutations in DHFR - gene can DHFR deficiency and this megaloblastic anemia cause.

The DHFR in protozoa and some plants is a double enzyme that also has the function of thymidylate synthase ; Because of this structural peculiarity, the protozoan DHFR is a target in the development of antibiotics, e.g. B. against the malaria pathogen Plasmodium falciparum or cryptosporidia .

Catalyzed reactions

The dihydrofolic acid reductase ( A ) catalyzes the reduction of 7,8-dihydrofolate ( 1 ) to tetrahydrofolate ( 2 ) while consuming NADPH . The enzyme can be competitively inhibited, for example, by methotrexate.

7,8-Dihydrofolic acid is reduced to tetrahydrofolic acid with NADPH as an electron donor (see fig.). In addition, folic acid can be reduced to DHF; however, this reaction is slower.

More functions

The presence of DHFR in endothelial cells is crucial for the function of tetrahydrobiopterin in NO synthase .

Regulation and inhibition

DHFR is an extensively studied enzyme that has been used as a target for chemotherapy and other diseases. The enzyme can be competitively inhibited by folic acid antagonists such as methotrexate , aminopterin or trimethoprim . The inhibition causes a deficiency in tetrahydrofolic acid, which prevents thymine synthesis ( thymidylate synthase requires THF) and purine synthesis (structure of the purine body), whereupon the cell dies.

See also

Individual evidence

  1. ↑ UniProt P00374
  2. ↑ Prosite entry
  3. ↑ Ochong E, Bell DJ, Johnson DJ, et al : Plasmodium falciparum strains harboring dihydrofolate reductase with the I164L mutation are absent in Malawi and Zambia even under antifolate drug pressure . In: Antimicrob. Agents Chemother. . 52, No. 11, November 2008, pp. 3883-8. doi : 10.1128 / AAC.00431-08 . PMID 18725445 .
  4. ↑ Bolstad DB, Bolstad ES, Frey KM, Wright DL, Anderson AC: Structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from cryptosporidium . In: J. Med. Chem. . 51, No. 21, November 2008, pp. 6839-52. doi : 10.1021 / jm8009124 . PMID 18834108 .
  5. ↑ EC  1.5.1.3
  6. ↑ Steven W Bailey, June E Ayling: The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake . In: Proceedings of the National Academy of Sciences . 106, No. 36, 2009, pp. 15424-15429.
  7. ↑ Chalupsky K, Cai H: Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase . In: Proc. Natl. Acad. Sci. USA . 102, No. 25, June 2005, pp. 9056-61. doi : 10.1073 / pnas.0409594102 . PMID 15941833 . PMC 1157015 (free full text).
  8. ↑ Abali EE, Skacel NE, Celikkaya H, Hsieh YC: Regulation of human dihydrofolate reductase activity and expression . In: Vitam. Horm. . 79, 2008, pp. 267-92. doi : 10.1016 / S0083-6729 (08) 00409-3 . PMID 18804698 .

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Dihydrofolate Reductase  - Learning and Teaching Materials