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Related Experiment Videos

Structure-based activity prediction for an enzyme of unknown function.

Johannes C Hermann1, Ricardo Marti-Arbona, Alexander A Fedorov

  • 1Department of Pharmaceutical Chemistry, University of California, San Francisco, MC 2550 1700 4th Street, San Francisco, California 94158-2330, USA.

Nature
|July 3, 2007
PubMed
Summary
This summary is machine-generated.

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Predicting protein function is challenging. This study used structure-based docking of metabolites to identify the function of enzyme Tm0936, revealing a novel S-adenosylhomocysteine degradation pathway.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Bioinformatics

Background:

  • Determining protein function is crucial, especially for proteins lacking homology to known enzymes.
  • Current bioinformatics methods struggle with inferring function for novel proteins.
  • Directly interrogating protein structures offers a potential solution for function prediction.

Purpose of the Study:

  • To predict the function of the enzyme Tm0936 from Thermotoga maritima using a structure-based approach.
  • To identify candidate substrates and enzymatic activity for Tm0936.
  • To elucidate a previously uncharacterized metabolic pathway in T. maritima.

Main Methods:

  • Structure-based docking of high-energy intermediate forms of thousands of candidate metabolites against the Tm0936 enzyme.

Related Experiment Videos

  • Experimental validation of predicted substrates, including kinetic assays.
  • X-ray crystallography to determine the structure of the enzyme-substrate complex.

    • Main Results:

    • Docking analysis predicted that Tm0936 catalyzes the C6-deamination of adenine analogues.
    • Four tested adenine analogues, including S-adenosylhomocysteine (SAH), showed significant catalytic activity (rate constants up to 10^5 M^-1 s^-1).
    • The crystal structure of Tm0936 with the SAH deamination product, S-inosylhomocysteine, confirmed the predicted binding mode and catalytic mechanism.

    Conclusions:

    • Structure-based docking with high-energy metabolite intermediates is an effective method for predicting enzyme function.
    • Tm0936 functions as an enzyme in a novel S-adenosylhomocysteine degradation pathway in Thermotoga maritima.
    • This approach provides a valuable tool for annotating enzymes and understanding metabolic pathways in newly sequenced genomes.