Insight into the reaction mechanism of lipoyl synthase : a QM/MM study
Dong, Geng LU ; Cao, Lili LU and Ryde, Ulf LU
(2018)
In Journal of Biological Inorganic Chemistry
23(2).
p.221-229
- 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.
(Less)
- author
- Dong, Geng
LU
; Cao, Lili
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2018-03
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Density functional theory, FeS cluster, Lipoyl synthase, QM/MM, Reaction mechanism, Spin state
- in
- Journal of Biological Inorganic Chemistry
- volume
- 23
- issue
- 2
- pages
- 221 - 229
- publisher
- Springer
- external identifiers
-
- pmid:29204715
- scopus:85036593774
- ISSN
- 0949-8257
- DOI
- 10.1007/s00775-017-1522-8
- project
- Computational Studies of Nitrogenase
- language
- English
- LU publication?
- yes
- id
- e438225b-e723-4861-9b03-ff519b4f9a4b
- date added to LUP
- 2017-12-18 08:40:17
- date last changed
- 2024-03-31 21:57:23
@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}},
keywords = {{Density functional theory; FeS cluster; Lipoyl synthase; QM/MM; Reaction mechanism; Spin state}},
language = {{eng}},
number = {{2}},
pages = {{221--229}},
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}},
doi = {{10.1007/s00775-017-1522-8}},
volume = {{23}},
year = {{2018}},
}