STRUCTURE OF AND KINETIC CHANNELING IN BIFUNCTIONAL DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE

The bifunctional enzyme dihydrofolate reductase-thymidylate synthase c atalyses both the reductive methylation of 2'-deoxyuridylate and the s ubsequent reduction of dihydrofolate to yield 2'-deoxythymidylate and tetrahydrofolate at two spacially discrete sites situated on different protein domains. The X-ray structure of dihydrofolate reductase-thymi dylate synthase from Leishmania major indicates that transfer of dihyd rofolate between these sites does not occur by transient binding at bo th sites but rather by movement of dihydrofolate across the surface of the protein. The enzyme has an unusual surface charge distribution th at could account for this channelling of dihydrofolate between active sites.