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

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Pedro J Silva (Author) Other; Maria Joao Ramos (Author) FCUP

Journal

Title: Journal of Physical Chemistry B

Vol. 112

Pages: 3144-3148

ISSN: 1520-6106

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 13 Citations

Scopus - 10 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-004-0WR

DOI: 10.1021/jp076235f

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 5