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Insight into the reaction mechanism of lipoyl synthase : a QM/MM study

Dong, Geng LU ; Cao, Lili LU and Ryde, Ulf LU (2017) In Journal of Biological Inorganic Chemistry
Abstract

Lipoyl synthase (LipA) catalyses the final step of the biosynthesis of the lipoyl cofactor by insertion of two sulfur atoms at the C6 and C8 atoms of the protein-bound octanoyl substrate. In this reaction, two [4Fe4S] clusters and two molecules of S-adenosyl-l-methionine are used. One of the two FeS clusters is responsible for the generation of a powerful oxidant, the 5′-deoxyadenosyl radical (5′-dA). The other (the auxiliary cluster) is the source of both sulfur atoms that are inserted into the substrate. In this paper, the spin state of the FeS clusters and the reaction mechanism is investigated by the combined quantum mechanical and molecular mechanics approach. The calculations show that the ground state of the two FeS... (More)

Lipoyl synthase (LipA) catalyses the final step of the biosynthesis of the lipoyl cofactor by insertion of two sulfur atoms at the C6 and C8 atoms of the protein-bound octanoyl substrate. In this reaction, two [4Fe4S] clusters and two molecules of S-adenosyl-l-methionine are used. One of the two FeS clusters is responsible for the generation of a powerful oxidant, the 5′-deoxyadenosyl radical (5′-dA). The other (the auxiliary cluster) is the source of both sulfur atoms that are inserted into the substrate. In this paper, the spin state of the FeS clusters and the reaction mechanism is investigated by the combined quantum mechanical and molecular mechanics approach. The calculations show that the ground state of the two FeS clusters, both in the [4Fe4S]2+ oxidation state, is a singlet state with antiferromagnetically coupled high-spin Fe ions and that there is quite a large variation of the energies of the various broken-symmetry states, up to 40 kJ/mol. For the two S-insertion reactions, the highest energy barrier is found for the hydrogen-atom abstraction from the octanoyl substrate by 5′-dA. The formation of 5′-dA is very facile for LipA, with an energy barrier of 6 kJ/mol for the first S-insertion reaction and without any barrier for the second S-insertion reaction. In addition, the first S ion attack on the C6 radical of octanoyl was found to take place directly by the transfer of the H6 from the substrate to 5′-dA, whereas for the second S-insertion reaction, a C8 radical intermediate was formed with a rate-limiting barrier of 71 kJ/mol.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Density functional theory, FeS cluster, Lipoyl synthase, QM/MM, Reaction mechanism, Spin state
in
Journal of Biological Inorganic Chemistry
pages
9 pages
publisher
Springer
external identifiers
  • scopus:85036593774
ISSN
0949-8257
DOI
10.1007/s00775-017-1522-8
language
English
LU publication?
yes
id
e438225b-e723-4861-9b03-ff519b4f9a4b
date added to LUP
2017-12-18 08:40:17
date last changed
2018-03-20 03:00:37
@article{e438225b-e723-4861-9b03-ff519b4f9a4b,
  abstract     = {<p>Lipoyl synthase (LipA) catalyses the final step of the biosynthesis of the lipoyl cofactor by insertion of two sulfur atoms at the C6 and C8 atoms of the protein-bound octanoyl substrate. In this reaction, two [4Fe4S] clusters and two molecules of S-adenosyl-l-methionine are used. One of the two FeS clusters is responsible for the generation of a powerful oxidant, the 5′-deoxyadenosyl radical (5′-dA<sup>•</sup>). The other (the auxiliary cluster) is the source of both sulfur atoms that are inserted into the substrate. In this paper, the spin state of the FeS clusters and the reaction mechanism is investigated by the combined quantum mechanical and molecular mechanics approach. The calculations show that the ground state of the two FeS clusters, both in the [4Fe4S]<sup>2+</sup> oxidation state, is a singlet state with antiferromagnetically coupled high-spin Fe ions and that there is quite a large variation of the energies of the various broken-symmetry states, up to 40 kJ/mol. For the two S-insertion reactions, the highest energy barrier is found for the hydrogen-atom abstraction from the octanoyl substrate by 5′-dA<sup>•</sup>. The formation of 5′-dA<sup>•</sup> is very facile for LipA, with an energy barrier of 6 kJ/mol for the first S-insertion reaction and without any barrier for the second S-insertion reaction. In addition, the first S ion attack on the C6 radical of octanoyl was found to take place directly by the transfer of the H6 from the substrate to 5′-dA<sup>•</sup>, whereas for the second S-insertion reaction, a C8 radical intermediate was formed with a rate-limiting barrier of 71 kJ/mol.</p>},
  author       = {Dong, Geng and Cao, Lili and Ryde, Ulf},
  issn         = {0949-8257},
  keyword      = {Density functional theory,FeS cluster,Lipoyl synthase,QM/MM,Reaction mechanism,Spin state},
  language     = {eng},
  month        = {12},
  pages        = {9},
  publisher    = {Springer},
  series       = {Journal of Biological Inorganic Chemistry},
  title        = {Insight into the reaction mechanism of lipoyl synthase : a QM/MM study},
  url          = {http://dx.doi.org/10.1007/s00775-017-1522-8},
  year         = {2017},
}