Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase

• Published in: Nature structural biology Vol. 1; no. 3; pp. 186 - 194
• Main Authors: Knighton, Daniel R, Kan, Chen-Chen, Howland, Eleanor, Janson, Cheryl A, Hostomska, Zuzana, Welsh, Katherine M, Matthews, David A
• Format: Journal Article
• Language: English
• Published: United States 01-03-1994
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Electrochemistry; Escherichia coli - enzymology; Escherichia coli - genetics; Humans; Kinetics; Leishmania major - enzymology; Leishmania major - genetics; Models, Molecular; Molecular Sequence Data; Molecular Structure; Multienzyme Complexes - chemistry; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Protein Conformation; Sequence Homology, Amino Acid; Tetrahydrofolate Dehydrogenase - chemistry; Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - metabolism; Thymidylate Synthase - chemistry; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism
• ISSN: 1072-8368; 2331-365X
• DOI: 10.1038/nsb0394-186

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.