Comparative density functional study of models for the reaction mechanism of uroporphyrinogen III synthase.

Abstract

The asymmetric cyclic tetrapyrrole uroporphyrinogen III is the common precursor of heme, chlorophyll, siroheme, and other biological tetrapyrroles. In vivo, it is synthesized from a linear symmetric precursor (hydroxymethylbilane) by uroporphyrinogen III synthase, which catalyzes the inversion of one of the four heterocyclic rings present in the substrate. Two mechanisms have been proposed to explain this puzzling ring inversion, either through sigmatropic shifts or through the direct formation of a spirocyclic pyrrolenine intermediate. We performed the first high-level quantum mechanical calculations on model systems of this enzyme to analyze these contrasting reaction mechanisms. The results allow us to discard the sigmatropic shift mechanism and suggest that the D-ring of the hydroxymethylbilane substrate binds to the enzyme in a conformation that shields its terminal portion from reacting with ring A and prevents the formation of the biologically useless uroporphyrinogen I, whose accumulation (in individuals lacking functional uroporphyrinogen III synthase) leads to severe cutaneous dermatosis.

• Authors: Pedro J Silva, Maria João Ramos
• Journal: The journal of physical chemistry. B (J Phys Chem B) Vol. 112 Issue 10 Pg. 3144-8 (Mar 13 2008) ISSN: 1520-6106 [Print] United States
• PMID: 18281969 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Spiro Compounds
• Uroporphyrinogen III Synthetase

Topics

• Catalysis
• Electrons
• Models, Biological
• Models, Molecular
• Molecular Structure
• Spiro Compounds (chemistry)
• Uroporphyrinogen III Synthetase (chemistry, metabolism)