Secondary H/D isotope effects and transition state looseness in nonidentity methyl transfer reactions. Implications for the concept of enzymic catalysis via transition state compression

1993 ◽  
Vol 115 (22) ◽  
pp. 10147-10152 ◽  
Author(s):  
Russell J. Boyd ◽  
Chan Kyung Kim ◽  
Zheng Shi ◽  
Noham Weinberg ◽  
Saul Wolfe
Keyword(s):  
Transition State ◽  
Isotope Effects ◽  
Transfer Reactions ◽  
Methyl Transfer

Additions and corrections: Transverse compression and the secondary H/D isotope effects in intramolecular SN2 methyl-transfer reactions

1998 ◽  
Vol 76 (3) ◽  
pp. 359-370 ◽  
Author(s):  
Saul Wolfe ◽  
Chan-Kyung Kim ◽  
Kiyull Yang ◽  
Noham Weinberg ◽  
Zheng Shi
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Isotope Effects ◽  
High Energy ◽  
Retention Mechanism ◽  
Sigmatropic Rearrangement ◽  
Orbital Theory ◽  
Bending Vibration ◽  
Kinetic Isotope ◽  
Methyl Transfer

Using ab initio molecular orbital theory mainly at the 3-21+G level, intramolecular SN2 methyl transfer between two oxygens confined within a rigid template is found to proceed exclusively by a high energy retention mechanism when the oxygens are separated by three or four bonds, and by a high energy inversion mechanism when the oxygens are separated by six bonds. Both mechanisms exist when the oxygens are separated by five bonds. The CH3/CD3 kinetic isotope effects are normal (1.21-1.34) in the retention processes and inverse (0.66-0.81) in the inversion reactions. In the case of inversion, compression of C-H bonds of the transition state by structural effects in the plane perpendicular to the O-C-O plane increases the inverse isotope effect. The retention barriers are high because retention is inherently unfavorable, even when pericyclic stabilization of the transition state is possible. The inversion barriers are high because a rigid template cannot accommodate a linear O-CH3 -O structure, and the O-C-O bending vibration is stiff (the Eschenmoser effect). Using a novel design strategy, a nonrigid template has been found in which the barrier and the CH3/CD3 kinetic isotope effect are the same as in an intermolecular reaction.Key words: Eschenmoser effect, isotope effect, compression, SN2, sigmatropic rearrangement.

scholarly journals Human DNMT1 transition state structure

2016 ◽  
Vol 113 (11) ◽  
pp. 2916-2921 ◽  
Author(s):  
Quan Du ◽  
Zhen Wang ◽  
Vern L. Schramm
Keyword(s):  
Transition State ◽  
Dna Methyltransferase ◽  
Catalytic Mechanism ◽  
Isotope Effects ◽  
Nucleophilic Attack ◽  
Kinetic Isotope ◽  
Methyl Transfer ◽  
Major Transition ◽  
Methylation Patterns ◽  
Rate Limiting

Human DNA methyltransferase 1 (DNMT1) maintains the epigenetic state of DNA by replicating CpG methylation signatures from parent to daughter strands, producing heritable methylation patterns through cell divisions. The proposed catalytic mechanism of DNMT1 involves nucleophilic attack of Cys1226 to cytosine (Cyt) C6, methyl transfer from S-adenosyl-l-methionine (SAM) to Cyt C5, and proton abstraction from C5 to form methylated CpG in DNA. Here, we report the subangstrom geometric and electrostatic structure of the major transition state (TS) of the reaction catalyzed by human DNMT1. Experimental kinetic isotope effects were used to guide quantum mechanical calculations to solve the TS structure. Methyl transfer occurs after Cys1226 attack to Cyt C6, and the methyl transfer step is chemically rate-limiting for DNMT1. Electrostatic potential maps were compared for the TS and ground states, providing the electronic basis for interactions between the protein and reactants at the TS. Understanding the TS of DNMT1 demonstrates the possibility of using similar analysis to gain subangstrom geometric insight into the complex reactions of epigenetic modifications.

.alpha.-Deuterium and carbon-13 isotope effects for methyl transfer catalyzed by catechol O-methyltransferase. SN2-like transition state

1979 ◽  
Vol 101 (15) ◽  
pp. 4359-4365 ◽  
Author(s):  
Mohamed F. Hegazi ◽  
Ronald T. Borchardt ◽  
Richard L. Schowen
Keyword(s):  
Transition State ◽  
Isotope Effects ◽  
Methyl Transfer

Ab initio studies on the correlation of force constant vs bond length in the transition state of methyl-transfer reactions

1990 ◽  
Vol 94 (12) ◽  
pp. 5190-5193 ◽  
Author(s):  
Ikchoon. Lee ◽  
Jeoung Ki. Cho ◽  
Ho Soon. Kim ◽  
Kwang Soo. Kim
Keyword(s):  
Transition State ◽  
Ab Initio ◽  
Bond Length ◽  
Force Constant ◽  
Transfer Reactions ◽  
Methyl Transfer
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