Dihydrofolate reductase (DHFR) () catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in de novosynthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [].Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar []. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown []to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [].
Dihydrofolate reductase (DHFR) () catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in de novosynthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [].Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar []. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown []to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [].This entry represents a plasmid-encoded DHFR which shows a high level of resistance to the antibiotic trimethoprim. It is a homotetramer with an unusual pore, which contains the active site, passing through the middle of the molecule []. Its structure is unrelated to that of chromosomal DHFRs.
Dihydrofolate reductase (DHFR) () catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in de novosynthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [].Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar []. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown []to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [].This entry covers the region in the N-terminal part of the DHFR domain, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme [].
Dihydrofolate reductase (DHFR) () catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, which can be used in de novosynthesis both certain amino acids, purines and deoxythymidine phosphate (the precursors of DNA synthesis) [], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [].Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar []. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown []to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [].
This group represents a bifunctional dihydrofolate reductase/thymidylate synthase found in some plant species and protozoal parasites including malarial species and trypanosomes. In other species dihydrofolate reductase and thymidilate synthase are encoded on separate polypeptides.Thymidylate synthase () []catalyzes the reductive methylation of dUMP to dTMP with concomitant conversion of 5,10-methylenetetrahydrofolate to dihydrofolate:5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMPThis provides the sole de novopathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer []. The enzyme is important for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process can cause various biological and genetic abnormalities. A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate). The sequence around the active site of this enzyme is conserved from phages to vertebrates.Dihydrofolate reductase (DHFR) () catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate:5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+This is an essential step in de novosynthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate.Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [].As this enzyme is essential in both nucleic acid and amino acid biosynthesis, it is an important target of antiparasitic drugs. Resistance to antimalarial drugs that target this enzyme is often due to mutations that prevent drug binding but maintain enzyme activity. The structure of the wild-type and drug resistant malarial enzymes provides insights into the development of resistance and suggests approaches for the design of new drugs against this target [].
