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The importance of porphyrin distortions for the ferrochelatase reaction.

Sigfridsson, Emma and Ryde, Ulf LU (2003) In Journal of Biological Inorganic Chemistry 8(3). p.273-282
Abstract
Ferrochelatase is the terminal enzyme in haem biosynthesis, i.e. the enzyme that inserts a ferrous ion into the porphyrin ring. Suggested reaction mechanisms for this enzyme involve a distortion of the porphyrin ring when it is bound to the enzyme. We have examined the energetics of such distortions using various theoretical calculations. With the density functional B3LYP method we calculate how much energy it costs to tilt one of the pyrrole rings out of the porphyrin plane for an isolated porphyrin molecule without or with a divalent metal ion in the centre of the ring. A tilt of 30° costs 65-130 kJ/mol for most metal ions, but only ~48 kJ/mol for free-base (neutral) porphine. This indicates that once the metal is inserted, the porphyrin... (More)
Ferrochelatase is the terminal enzyme in haem biosynthesis, i.e. the enzyme that inserts a ferrous ion into the porphyrin ring. Suggested reaction mechanisms for this enzyme involve a distortion of the porphyrin ring when it is bound to the enzyme. We have examined the energetics of such distortions using various theoretical calculations. With the density functional B3LYP method we calculate how much energy it costs to tilt one of the pyrrole rings out of the porphyrin plane for an isolated porphyrin molecule without or with a divalent metal ion in the centre of the ring. A tilt of 30° costs 65-130 kJ/mol for most metal ions, but only ~48 kJ/mol for free-base (neutral) porphine. This indicates that once the metal is inserted, the porphyrin becomes stiffer and flatter, and therefore binds with lower affinity to a site designed to bind a distorted porphyrin. This would facilitate the release of the product from ferrochelatase. This proposal is strengthened by the fact that the only tested metal ion with a lower distortion energy than free-base porphyrin (Cd2+) is an inhibitor of ferrochelatase. Moreover, it costs even less energy to tilt a doubly deprotonated porphine2- molecule. This suggests that the protein may lower the acid constant of the pyrrole nitrogen atoms by deforming the porphyrin molecule. We have also estimated the structure of the protoporphyrin IX substrate bound to ferrochelatase using combined quantum chemical and molecular mechanics calculations. The result shows that the protein may distort the porphyrin by ~20 kJ/mol, leading to a distinctly non-planar structure. All four pyrrole rings are tilted out of the porphyrin mean plane (1-16°) but most towards the putative binding site of the metal ion. The predicted tilt is considerably smaller than that observed in the crystal structure of a porphyrin inhibitor. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ferrochelatase Æ Density functional calculation Æ QM/MM calculations Æ Porphyrin distortion Æ Potential-of-mean-force calculation
in
Journal of Biological Inorganic Chemistry
volume
8
issue
3
pages
273 - 282
publisher
Springer
external identifiers
  • wos:000181365200005
  • pmid:12589563
  • scopus:0037329044
ISSN
1432-1327
DOI
language
English
LU publication?
yes
id
d8122cf7-0247-4369-808c-e87ab2747823 (old id 128843)
date added to LUP
2007-07-17 14:09:09
date last changed
2018-05-29 12:03:49
@article{d8122cf7-0247-4369-808c-e87ab2747823,
  abstract     = {Ferrochelatase is the terminal enzyme in haem biosynthesis, i.e. the enzyme that inserts a ferrous ion into the porphyrin ring. Suggested reaction mechanisms for this enzyme involve a distortion of the porphyrin ring when it is bound to the enzyme. We have examined the energetics of such distortions using various theoretical calculations. With the density functional B3LYP method we calculate how much energy it costs to tilt one of the pyrrole rings out of the porphyrin plane for an isolated porphyrin molecule without or with a divalent metal ion in the centre of the ring. A tilt of 30° costs 65-130 kJ/mol for most metal ions, but only ~48 kJ/mol for free-base (neutral) porphine. This indicates that once the metal is inserted, the porphyrin becomes stiffer and flatter, and therefore binds with lower affinity to a site designed to bind a distorted porphyrin. This would facilitate the release of the product from ferrochelatase. This proposal is strengthened by the fact that the only tested metal ion with a lower distortion energy than free-base porphyrin (Cd2+) is an inhibitor of ferrochelatase. Moreover, it costs even less energy to tilt a doubly deprotonated porphine2- molecule. This suggests that the protein may lower the acid constant of the pyrrole nitrogen atoms by deforming the porphyrin molecule. We have also estimated the structure of the protoporphyrin IX substrate bound to ferrochelatase using combined quantum chemical and molecular mechanics calculations. The result shows that the protein may distort the porphyrin by ~20 kJ/mol, leading to a distinctly non-planar structure. All four pyrrole rings are tilted out of the porphyrin mean plane (1-16°) but most towards the putative binding site of the metal ion. The predicted tilt is considerably smaller than that observed in the crystal structure of a porphyrin inhibitor.},
  author       = {Sigfridsson, Emma and Ryde, Ulf},
  issn         = {1432-1327},
  keyword      = {Ferrochelatase Æ Density functional
calculation Æ QM/MM calculations Æ Porphyrin
distortion Æ Potential-of-mean-force calculation},
  language     = {eng},
  number       = {3},
  pages        = {273--282},
  publisher    = {Springer},
  series       = {Journal of Biological Inorganic Chemistry},
  title        = {The importance of porphyrin distortions for the ferrochelatase reaction.},
  url          = {http://dx.doi.org/},
  volume       = {8},
  year         = {2003},
}