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Structural insight into acute intermittent porphyria

Gaojie Song1, Yang Li, Chongyun Cheng

  • 1National Laboratory of Biomacromolecules, Institute of Biophysics, 15 Datun Lu, Beijing 100101, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|October 22, 2008
PubMed

Insights

Acute intermittent porphyria (AIP) is linked to reduced porphobilinogen deaminase (PBGD) activity. The 3D structure of human PBGD reveals its catalytic mechanism, aiding potential drug development for AIP.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Genetics

Background:

  • Acute intermittent porphyria (AIP) is a common inherited disorder of heme biosynthesis.
  • Reduced activity of porphobilinogen deaminase (PBGD) is associated with AIP symptoms.

Purpose of the Study:

  • To determine the 3-dimensional structure of human PBGD.
  • To elucidate the molecular mechanism of PBGD catalysis and its relation to AIP.

Main Methods:

  • X-ray crystallography to determine the 3D structure of human PBGD at 2.2 A resolution.
  • Structural analysis to identify key residues, cofactor interactions, and domain movements.

Main Results:

  • The 3D structure revealed a dipyrromethane cofactor linked to C261 in a positively charged cleft.
  • Catalytic residues (D99) and hinge residues (H120) were identified, with H120P mutation causing inactivation.
  • Some AIP-associated mutations are located distant from the active site, suggesting complex regulatory mechanisms.

Conclusions:

  • The determined structure provides molecular insights into PBGD's mechanism of action.
  • Understanding PBGD structure and function can guide the development of novel therapeutics for AIP aimed at up-regulating enzyme activity.

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