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A novel mechanism of heme degradation to biliverdin studied by QM/MM and QM calculations

Alavi, Fatemeh Sadat ; Gheidi, Mahin ; Zahedi, Mansour ; Safari, Nasser and Ryde, Ulf LU orcid (2018) In Dalton Transactions 47(25). p.8283-8291
Abstract

Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress. Previous studies have reported that heme degradation proceeds through three consecutive steps of O2 activation: the regiospecific self-hydroxylation of heme, the conversion of hydroxyheme to verdoheme and CO, and the cleavage of the verdoheme macrocycle to release biliverdin and free ferrous iron. Our results indicate that in the second step of heme degradation, not only verdoheme is generated but ring opening and biliverdin production also occur. We have performed QM-cluster and QM/MM calculations, which show that calculations with H2O as the axial ligand of Fe give the lowest barrier. In... (More)

Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress. Previous studies have reported that heme degradation proceeds through three consecutive steps of O2 activation: the regiospecific self-hydroxylation of heme, the conversion of hydroxyheme to verdoheme and CO, and the cleavage of the verdoheme macrocycle to release biliverdin and free ferrous iron. Our results indicate that in the second step of heme degradation, not only verdoheme is generated but ring opening and biliverdin production also occur. We have performed QM-cluster and QM/MM calculations, which show that calculations with H2O as the axial ligand of Fe give the lowest barrier. In the QM-cluster calculation, the reaction is exothermic by -85 kcal mol-1 and the rate-limiting barrier is 5 kcal mol-1, whereas the corresponding QM/MM calculations give a slightly lower barrier of 3 kcal mol-1, owing to strong hydrogen bonds and the protein environment.

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Please use this url to cite or link to this publication:
author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Dalton Transactions
volume
47
issue
25
pages
9 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85049016958
  • pmid:29892759
ISSN
1477-9226
DOI
10.1039/c8dt00064f
language
English
LU publication?
yes
id
a3f0b01e-8036-4ee5-aeef-b9db5833b9d7
date added to LUP
2018-07-06 13:53:01
date last changed
2021-09-22 04:17:11
@article{a3f0b01e-8036-4ee5-aeef-b9db5833b9d7,
  abstract     = {<p>Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress. Previous studies have reported that heme degradation proceeds through three consecutive steps of O<sub>2</sub> activation: the regiospecific self-hydroxylation of heme, the conversion of hydroxyheme to verdoheme and CO, and the cleavage of the verdoheme macrocycle to release biliverdin and free ferrous iron. Our results indicate that in the second step of heme degradation, not only verdoheme is generated but ring opening and biliverdin production also occur. We have performed QM-cluster and QM/MM calculations, which show that calculations with H<sub>2</sub>O as the axial ligand of Fe give the lowest barrier. In the QM-cluster calculation, the reaction is exothermic by -85 kcal mol<sup>-1</sup> and the rate-limiting barrier is 5 kcal mol<sup>-1</sup>, whereas the corresponding QM/MM calculations give a slightly lower barrier of 3 kcal mol<sup>-1</sup>, owing to strong hydrogen bonds and the protein environment.</p>},
  author       = {Alavi, Fatemeh Sadat and Gheidi, Mahin and Zahedi, Mansour and Safari, Nasser and Ryde, Ulf},
  issn         = {1477-9226},
  language     = {eng},
  month        = {01},
  number       = {25},
  pages        = {8283--8291},
  publisher    = {Royal Society of Chemistry},
  series       = {Dalton Transactions},
  title        = {A novel mechanism of heme degradation to biliverdin studied by QM/MM and QM calculations},
  url          = {https://lup.lub.lu.se/search/files/57285199/238_fatima2.pdf},
  doi          = {10.1039/c8dt00064f},
  volume       = {47},
  year         = {2018},
}