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Related Experiment Videos

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase.

J S Finer-Moore1, W R Montfort, R M Stroud

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.

Biochemistry
|July 31, 1990
PubMed
Summary
This summary is machine-generated.

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Thymidylate synthase (TS) structures reveal a stereochemical model for its reaction intermediate. This model clarifies the enzyme's catalytic mechanism and the roles of specific amino acid residues.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Thymidylate synthase (TS) is crucial for DNA synthesis, catalyzing the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP).
  • Understanding the catalytic mechanism of TS is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the stereochemical mechanism of thymidylate synthase (TS) catalysis.
  • To develop a stereochemical model for a key reaction intermediate based on structural data.
  • To identify key amino acid residues involved in the catalytic process.

Main Methods:

  • X-ray crystallography of Escherichia coli TS in ternary complexes with substrate and cofactor analogue.
  • Stereochemical analysis of the transferred methyl group.

Related Experiment Videos

  • Correlation of enzyme structure with effects of chemical modification and site-directed mutagenesis.

    • Main Results:

    • A stereochemical model for a key TS reaction intermediate was established.
    • The ordered binding of deoxyuridine monophosphate and methylenetetrahydrofolate was explained by their interactions within the active site.
    • The active site's structure was shown to sequester reactants and water molecules, facilitating catalysis.

    Conclusions:

    • The study provides insights into the precise orientation of reactants within the active site.
    • Conformational changes involving nearby residues may play a role in the catalytic mechanism.
    • Structural data supports a detailed stereochemical mechanism for thymidylate synthase.