Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase.
The bifunctional enzyme dihydrofolate reductase-thymidylate synthase catalyses both the reductive methylation of 2'-deoxyuridylate and the subsequent 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-thymidylate synthase from Leishmania major indicates that transfer of dihydrofolate between these sites does not occur by transient binding at both sites but rather by movement of dihydrofolate across the surface of the protein. The enzyme has an unusual surface charge distribution that could account for this channelling of dihydrofolate between active sites.
Knighton
D R
DR
Agouron Pharmaceuticals, Inc., San Diego, California 92121-1122, USA.
Kan
C C
CC
Howland
E
E
Janson
C A
CA
Hostomska
Z
Z
Welsh
K M
KM
Matthews
D A
DA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004563:Electrochemistry; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007700:Kinetics; D018320:Leishmania major / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase