Bifunctional dihydrofolate reductase-thymidylate synthase

Function

Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.

Classification

Family (Pfam)

PF00186 DHFR_1, PF00303 Thymidylat_synt

InterPro

DHFR-like_dom_sf, DHFR-TS, DHFR_CS, DHFR_dom, Thymidate_synth/dCMP_Mease, Thymidate_synth/dCMP_Mease_dom, Thymidate_synth/dCMP_Mease_sf, Thymidylate_synthase, Thymidylate_synthase_AS

Functional cluster

RNase H & Viral Replication Proteins

Experimental structures · PDB · 9

• 1J3I X-ray 2.33A
• 1J3J X-ray 2.30A
• 1J3K X-ray 2.10A
• 3DG8 X-ray 2.58A
• 3DGA X-ray 2.70A
• 7CTW X-ray 2.51A
• 7F3Y X-ray 2.25A
• 7F3Z X-ray 2.60A
• 8WGM X-ray 2.15A

A predicted model is available from AlphaFold.

Gene Ontology · 8

• GO:0005829 cytosol
• GO:0005739 mitochondrion
• GO:0004146 dihydrofolate reductase activity
• GO:0004799 thymidylate synthase activity
• GO:0006231 dTMP biosynthetic process
• GO:0032259 methylation
• GO:0006730 one-carbon metabolic process
• GO:0046654 tetrahydrofolate biosynthetic process

Drugs targeting this protein · 3

• PROGUANIL HYDROCHLORIDE inhibitor
• PYRIMETHAMINE inhibitor
• CYCLOGUANIL PAMOATE inhibitor

Related proteins · sequence + function similarity

• Bifunctional dihydrofolate reductase-thymidylate synthase 0.96
• Bifunctional dihydrofolate reductase-thymidylate synthase 0.87
• Bifunctional dihydrofolate reductase-thymidylate synthase 0.80
• Probable inorganic pyrophosphatase 0.80
• Bifunctional glucose-6-phosphate 1-dehydrogenase/6-phosphogluconolactonase 0.80
• DNA-(apurinic or apyrimidinic site) endonuclease 0.78
• Serine--tRNA ligase, cytoplasmic 0.78
• Plastidic DNA replication/repair enzyme complex 0.78
• Dual specificity protein phosphatase YVH1 0.77
• tRNA (guanine(37)-N(1))-methyltransferase 0.77
• Translation factor GUF1 homolog, mitochondrial 0.77
• DNA-(apurinic or apyrimidinic site) endonuclease 0.77

Literature · 6 cited papers

• Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria. ACS Chem. Biol. · 2009
• Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol. · 2003
• Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. U.S.A. · 1988
• Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene. Proc. Natl. Acad. Sci. U.S.A. · 1987
• Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum. Mol. Biochem. Parasitol. · 1989
• Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine. Gene · 1989