A comparative density-functional study of the reaction mechanism of the O2-dependent coproporphyrinogen III oxidase.

Abstract

During heme biosynthesis, coproporphyrinogen III oxidase catalyzes the conversion of two propionate substituents from the highly reactive substrate coproporphyrinogen III into vinyl substituents, yielding protoporphyrinogen IX. Although the crystal structure of this important enzyme has recently been reported, the reaction mechanism of this intriguing enzyme remains the subject of intense speculation, as impairment of this enzyme has been shown to be the molecular cause behind hereditary coproporphyria. We have performed DFT calculations on model systems in order to analyze several reaction mechanisms proposed for this enzyme. The results afford a full description of the different proposals and allow the rejection of a direct electron abstraction from the protonated substrate by dioxygen. We found that O(2) addition to the (preferentially deprotonated) pyrrole substrate (yielding a hydroperoxide, which then abstracts a proton from the reactive propionate substituent) is compatible with the observed experimental reaction rate, and that the reaction may then proceed through HO2- elimination, followed by decarboxylation.

• Authors: Pedro J Silva, Maria João Ramos
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 6 Pg. 2726-33 (Mar 15 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18226911 (Publication Type: Journal Article)

Chemical References

• Protons
• Pyrroles
• Heme
• Hydrogen Peroxide
• Coproporphyrinogen Oxidase
• Oxygen

Topics

• Catalysis
• Coproporphyrinogen Oxidase (chemistry, metabolism)
• Decarboxylation
• Heme (biosynthesis)
• Hydrogen Peroxide
• Kinetics
• Models, Molecular
• Oxygen (chemistry)
• Protons
• Pyrroles