Thymidylate synthase-dihydrofolate reductase in protozoa.
In protozoa, thymidylate synthase (TS) and dihydrofolate reductase (DHFR) exist on the same polypeptide. The DHFR domain is on the amino terminus, TS is on the carboxy terminus, and the domains are separated by a junction peptide of varying size depending on the source. The native protein is a dimer of two such subunits and is 110-140 kDa. Most studies of bifunctional TS-DHFR have been performed with the protein from anti-folate resistant strains of Leishmania major, which show amplification of the TS-DHFR gene and overproduction of the bifunctional protein. The Leishmania TS-DHFR has also been highly expressed in heterologous systems. There is extensive communication between domains, and channeling of the H2folate product of TS to DHFR. Anti-folates commonly used to treat microbial infections are poor inhibitors of L. major DHFR. However, selective inhibitors of L. major vs human DHFR have been found. The TS-DHFR from Plasmodium falciparum has also been cloned and sequenced. Interestingly, pyrimethamine-resistant strains of P. falciparum have a common point mutation in the DHFR coding sequence which causes decreased binding of the folate analog. A detailed knowledge of the structure and function of protozoan TS-DHFRs will soon be available.
Ivanetich
K M
KM
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.
Santi
D V
DV
D000818:Animals; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D005493:Folic Acid Antagonists; D007891:Leishmania / Q000201:enzymology* / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D010961:Plasmodium / Q000201:enzymology* / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D005493:Folic Acid Antagonists; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013938:Thymidine Monophosphate; C010920:dihydrofolate; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase