Browse by author
Lookup NU author(s): Professor Alan Calvert
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Thymidylate synthase (TS) catalyzes the final step in the de novo synthesis of thymidine. In vivo TS binds a polyglutamyl cofactor, polyglutamyl methylenetetrahydrofolate (CH2-H4folate), which serves as a carbon donor. Glutamate residues on the cofactor contribute as much as 3.7 kcal to the interaction between the cofactor, substrate, and enzyme. Because many ligand/receptor interactions appear to be driven largely by hydrophobic forces, it is surprising that the addition of hydrophilic, soluble groups such as glutamates increases the affinity of the cofactor for TS. The structure of a polyglutamyl cofactor analog bound in ternary complex with deoxyuridine monophosphate (dUMP) and Escherichia coli TS reveals how the polyglutamyl moiety is positioned in TS and accounts in a qualitative way for the binding contributions of the different individual glutamate residues. The polyglutamyl moiety is not rigidly fixed by its interaction with the protein except for the first glutamate residue nearest the p-aminobenzoic acid ring of folate. Each additional glutamate is progressively more disordered than the previous one in the chain. The position of the second and third glutamate residues on the protein surface suggests that the polyglutamyl binding site could be utilized by a new family of inhibitors that might fill the binding area more effectively than polyglutamate.
Author(s): Kamb A, Moore JF, Calvert AH, Stroud RM
Publication type: Article
Publication status: Published
Journal: Biochemistry
Year: 1992
Volume: 31
Issue: 41
Pages: 9883-9890
Print publication date: 20/10/1992
ISSN (print): 0006-2960
ISSN (electronic): 1520-4995
URL: http://dx.doi.org/10.1021/bi00156a005
DOI: 10.1021/bi00156a005
PubMed id: 1390771
Altmetrics provided by Altmetric
