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231224s2011 xx |||||o 00| ||eng c |
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|a 10.1002/jcc.21895
|2 doi
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|a pubmed25n0702.xml
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|a (DE-627)NLM210714239
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|a (NLM)21837727
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|a DE-627
|b ger
|c DE-627
|e rakwb
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|a eng
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1 |
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|a Abdel-Azeim, Safwat
|e verfasserin
|4 aut
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|a Zinc-homocysteine binding in cobalamin-dependent methionine synthase and its role in the substrate activation
|b DFT, ONIOM, and QM/MM molecular dynamics studies
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|c 2011
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|a Text
|b txt
|2 rdacontent
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|a ƒaComputermedien
|b c
|2 rdamedia
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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|a Date Completed 21.02.2012
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|a Date Revised 11.03.2022
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|a published: Print-Electronic
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|a Citation Status MEDLINE
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|a Copyright © 2011 Wiley Periodicals, Inc.
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|a Cobalamin-dependent methionine synthase (MetH) is an important metalloenzyme responsible for the biosynthesis of methionine. It catalyzes methyl transfer from N(5)-methyl-tetrahydrofolate to homocysteine (Hcy) by using a zinc ion to activate the Hcy substrate. Density functional theory (B3LYP) calculations on the active-site model in gas phase and in a polarized continuum model were performed to study the Zn coordination changes from the substrate-unbound state to the substrate-bound state. The protein effect on the Zn(2+) coordination exchange was further investigated by ONIOM (B3LYP:AMBER)-ME and EE calculations. The Zn(2+)-coordination exchange is found to be highly unfavorable in the gas phase with a high barrier and endothermicity. In the water solution, the reaction becomes exothermic and the reaction barrier is drastically decreased to about 10.0 kcal/mol. A considerable protein effect on the coordination exchange was also found; the reaction is even more exothermic and occurs without barrier. The enzyme was suggested to constrain the zinc coordination sphere in the reactant state (Hcy-unbound state) more than that in the product state (Hcy-bound state), which promotes ligation of the Hcy substrate. Molecular dynamics simulations using molecular mechanics (MM) and PM3/MM potentials suggest a correlation between the flexibility of the Zn(2+)-binding site and regulation of the enzyme function. Directed in silico mutations of selected residues in the active site were also performed. Our studies support a dissociative mechanism starting with the Zn-O(Asn234) bond breaking followed by the Zn-S((Hcy)) bond formation; the proposed associative mechanism for the Zn(2+)-coordination exchange is not supported
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|a Journal Article
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|a Research Support, Non-U.S. Gov't
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|a Homocysteine
|2 NLM
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|a 0LVT1QZ0BA
|2 NLM
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|a 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
|2 NLM
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| 650 |
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|a EC 2.1.1.13
|2 NLM
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| 650 |
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|a Zinc
|2 NLM
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| 650 |
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|a J41CSQ7QDS
|2 NLM
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| 650 |
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|a Vitamin B 12
|2 NLM
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| 650 |
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|a P6YC3EG204
|2 NLM
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| 700 |
1 |
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|a Li, Xin
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Chung, Lung Wa
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Morokuma, Keiji
|e verfasserin
|4 aut
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| 773 |
0 |
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|i Enthalten in
|t Journal of computational chemistry
|d 1984
|g 32(2011), 15 vom: 30. Nov., Seite 3154-67
|w (DE-627)NLM098138448
|x 1096-987X
|7 nnns
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| 773 |
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|g volume:32
|g year:2011
|g number:15
|g day:30
|g month:11
|g pages:3154-67
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|u http://dx.doi.org/10.1002/jcc.21895
|3 Volltext
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|d 32
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|h 3154-67
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