Catalytic mechanism of porphobilinogen synthase: the chemical step revisited by QM/MM calculations.

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  • Author(s): Tian BX;Tian BX; Erdtman E; Eriksson LA
  • Source:
    The journal of physical chemistry. B [J Phys Chem B] 2012 Oct 11; Vol. 116 (40), pp. 12105-12. Date of Electronic Publication: 2012 Oct 02.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Chemical Society, c1997-
    • Subject Terms:
      Quantum Theory*; Aminolevulinic Acid/*metabolism ; Porphobilinogen Synthase/*metabolism; Aminolevulinic Acid/chemistry ; Biocatalysis ; Cyclization ; Molecular Structure ; Porphobilinogen Synthase/chemistry
    • Abstract:
      Porphobilinogen synthase (PBGS) catalyzes the asymmetric condensation and cyclization of two 5-aminolevulinic acid (5-ALA) substrate molecules to give porphobilinogen (PBG). The chemical step of PBGS is herein revisited using QM/MM (ONIOM) calculations. Two different protonation states and several different mechanisms are considered. Previous mechanisms based on DFT-only calculations are shown unlikely to occur. According to these new calculations, the deprotonation step rather than ring closure is rate-limiting. Both the C-C bond formation first mechanism and the C-N bond formation first mechanism are possible, depending on how the A-site ALA binds to the enzyme. We furthermore propose that future work should focus on the substrate binding step rather than the enzymatic mechanism.
    • Accession Number:
      88755TAZ87 (Aminolevulinic Acid)
      EC 4.2.1.24 (Porphobilinogen Synthase)
    • Publication Date:
      Date Created: 20120915 Date Completed: 20130225 Latest Revision: 20131121
    • Publication Date:
      20231215
    • Accession Number:
      10.1021/jp304743c
    • Accession Number:
      22974111