title: Homology modelling of the dihydrofolate reductase-thymidylate synthase bifunctional enzyme of Leishmania major, a potential target for rational drug design in leishmaniasis.
abstract: A homology model of the dimeric Leishmania major dihydrofolate reductase-thymidylate synthase bifunctional enzyme was built based upon the available crystallographic structures of the dihydrofolate reductase and thymidylate synthase monofunctional enzymes. The corresponding substrates, cofactors and inhibitors of the monofunctional enzymes were modelled in the active-sites of the homodimeric model of the bifunctional enzyme. The small number of residues in the interdomain region of the L. major sequence, compared to the other DHFR-TS sequences, imposed severe constraints on the relative locations of the two functional domains. The DHFR and TS domains in the malarial, trypanosomal and toxoplasmia structures are likely to have comparable locations. The leishmanial model reveals features which may be of use in designing novel antifolates for leishmaniasis and protozoal parasites in general.
authors.affiliation: Department of Pharmacy, University of Manchester, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: McKie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D005493:Folic Acid Antagonists; D018320:Leishmania major / Q000201:enzymology*; D007896:Leishmaniasis / Q000188:drug therapy*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase