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Related Experiment Videos

Structural studies on porphobilinogen deaminase

R Lambert1, P D Brownlie, S C Woodcock

  • 1Department of Crystallography, Birkbeck College, London, UK.

Ciba Foundation Symposium
|January 1, 1994
PubMed
Summary

X-ray crystallography reveals the three-domain structure of porphobilinogen deaminase. Structural analysis of enzyme active site mutations clarifies its role in the polymerization reaction.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Porphobilinogen deaminase (PBG-D), also known as hydroxymethylbilane synthase (EC 4.3.1.8), is crucial for heme biosynthesis.
  • Understanding PBG-D's structure is key to elucidating its catalytic mechanism and potential therapeutic targets.

Purpose of the Study:

  • To determine the three-dimensional structure of porphobilinogen deaminase using X-ray crystallography.
  • To investigate the role of specific amino acid residues and cofactor interactions in enzyme activity.
  • To analyze the structural consequences of site-directed mutagenesis on enzyme function.

Main Methods:

  • X-ray crystallographic analysis of wild-type and mutant porphobilinogen deaminase.
  • Site-directed mutagenesis to alter active site residues (e.g., arginine to histidine, aspartic acid to glutamic acid).

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  • Structural and kinetic studies to correlate protein structure with enzyme function.

    • Main Results:

    • The polypeptide chain of PBG-D folds into three distinct domains (N-terminal, central, C-terminal).
    • Domains 1 and 2 share a similar topology (modified doubly wound parallel beta-sheet), while domain 3 is an antiparallel beta-sheet with alpha-helices.
    • The active site, located between domains 1 and 2, contains a dipyrromethane cofactor and conserved arginine residues; Aspartic acid 84 is identified as a critical catalytic residue.

    Conclusions:

    • The multi-domain structure of PBG-D facilitates conformational changes essential for its catalytic activity.
    • Mutagenesis studies confirm the critical roles of Aspartic acid 84 and active site arginines in the enzyme's polymerization function.
    • Structural insights into PBG-D mutants provide a basis for understanding enzyme mechanism and guiding future drug design.