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Citation
Tags
HERO ID
3044646
Reference Type
Journal Article
Title
Density functional theory calculations on the active site of biotin synthase: mechanism of S transfer from the Fe2S2 cluster and the role of 1st and 2nd sphere residues
Author(s)
Rana, A; Dey, S; Agrawal, A; Dey, A
Year
2015
Is Peer Reviewed?
Yes
Journal
Journal of Biological Inorganic Chemistry
ISSN:
0949-8257
EISSN:
1432-1327
Volume
20
Issue
7
Page Numbers
1147-1162
Language
English
PMID
26369537
DOI
10.1007/s00775-015-1296-9
Abstract
Density functional theory (DFT) calculations are performed on the active site of biotin synthase (BS) to investigate the sulfur transfer from the Fe2S2 cluster to dethiobiotin (DTB). The active site is modeled to include both the 1st and 2nd sphere residues. Molecular orbital theory considerations and calculation on smaller models indicate that only an S atom (not S(2-)) transfer from an oxidized Fe2S2 cluster leads to the formation of biotin from the DTB using two adenosyl radicals generated from S-adenosyl-L-methionine. The calculations on larger protein active site model indicate that a 9-monothiobiotin bound reduced cluster should be an intermediate during the S atom insertion from the Fe2S2 cluster consistent with experimental data. The Arg260 bound to Fe1, being a weaker donor than cysteine bound to Fe2, determines the geometry and the electronic structure of this intermediate. The formation of this intermediate containing the C9-S bond is estimated to have a ΔG(≠) of 17.1 kcal/mol while its decay by the formation of the 2nd C6-S bond is calculated to have a ΔG(≠) of 29.8 kcal/mol, i.e. the 2nd C-S bond formation is calculated to be the rate determining step in the cycle and it leads to the decay of the Fe2S2 cluster. Significant configuration interaction (CI), present in these transition states, helps lower the barrier of these reactions by ~30-25 kcal/mol relative to a hypothetical outer-sphere reaction. The conserved Phe285 residue near the Fe2S2 active site determines the stereo selectivity at the C6 center of this radical coupling reaction. Reaction mechanism of BS investigated using DFT calculations. Strong CI and the Phe285 residue control the kinetic rate and stereochemistry of the product.
Tags
IRIS
•
Trimethylbenzenes (Interagency Science Discussion Draft)
Literature Search Update
Literature Search Update- Excluded
Excluded by Title/Abstract
Non-relevant Biological System or Chemical
•
Trimethylbenzenes (TMB)
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