Water-assisted oxo mechanism for heme metabolism

Takashi Kamachi, Kazunari Yoshizawa

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the α-carbon by the iron-hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the α-carbon by an iron-oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results.

Original languageEnglish
Pages (from-to)10686-10692
Number of pages7
JournalJournal of the American Chemical Society
Volume127
Issue number30
DOIs
Publication statusPublished - Aug 3 2005

Fingerprint

Heme
Metabolism
Porphyrins
Heme Oxygenase (Decyclizing)
Water
Oxidation
Carbon
Iron
Activation energy
Chemical activation
Proteins
Molecules
Density functional theory
Enzymes
Atoms
Oxygenases

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Water-assisted oxo mechanism for heme metabolism. / Kamachi, Takashi; Yoshizawa, Kazunari.

In: Journal of the American Chemical Society, Vol. 127, No. 30, 03.08.2005, p. 10686-10692.

Research output: Contribution to journalArticle

@article{44dbe6a9d6d441ee8060923c5472d5e4,
title = "Water-assisted oxo mechanism for heme metabolism",
abstract = "A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the α-carbon by the iron-hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the α-carbon by an iron-oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results.",
author = "Takashi Kamachi and Kazunari Yoshizawa",
year = "2005",
month = "8",
day = "3",
doi = "10.1021/ja051912+",
language = "English",
volume = "127",
pages = "10686--10692",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "30",

}

TY - JOUR

T1 - Water-assisted oxo mechanism for heme metabolism

AU - Kamachi, Takashi

AU - Yoshizawa, Kazunari

PY - 2005/8/3

Y1 - 2005/8/3

N2 - A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the α-carbon by the iron-hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the α-carbon by an iron-oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results.

AB - A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the α-carbon by the iron-hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the α-carbon by an iron-oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results.

UR - http://www.scopus.com/inward/record.url?scp=23044434960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23044434960&partnerID=8YFLogxK

U2 - 10.1021/ja051912+

DO - 10.1021/ja051912+

M3 - Article

C2 - 16045356

AN - SCOPUS:23044434960

VL - 127

SP - 10686

EP - 10692

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 30

ER -