PMID- 18512960
OWN - NLM
STAT- MEDLINE
DCOM- 20100507
LR  - 20190816
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 47
IP  - 25
DP  - 2008 Jun 24
TI  - Product specificity and mechanism of protein lysine methyltransferases: insights 
      from the histone lysine methyltransferase SET8.
PG  - 6671-7
LID - 10.1021/bi800244s [doi]
AB  - Molecular dynamics simulations employing a molecular mechanics (MM) force field 
      and hybrid quantum mechanics (QM) and MM (QM/MM) have been carried out to 
      investigate the product specificity and mechanism of the histone H4 lysine 20 
      (H4-K20) methylation by human histone lysine methyltransferase SET8. At neutral 
      pH, the target lysine is available to only the enzyme in the protonated state. 
      The first step in the methylation reaction must be deprotonation of the lysine 
      target which is followed by the (+)AdoMet methylation of the neutral lysine 
      [Enz.Lys-CH(2)-NH(3)(+).(+)AdoMet --> H(+) + Enz.Lys-CH(2)-NH(2).(+)AdoMet -->--> 
      Enz.Lys-CH(2)-N(Me)H(2)(+).AdoHcy]. The electrostatic interactions between two 
      positive charges on (+)AdoMet and Lys20-NH(3)(+) decrease the pK(a) of 
      Lys20-NH(3)(+). Upon formation of Enz.Lys-NH(3)(+).(+)AdoMet, a water channel by 
      which the proton escapes to the outer solvent phase is formed. The formation of a 
      water channel for the escape of a proton from Lys20-N(Me)H(2)(+) in 
      Enz.Lys20-N(Me)H(2)(+).(+)AdoMet is not formed because the methyl substituent 
      blocks the starting of the water channel. Thus, a second methylation does not 
      take place. The dependence of the occurrence of methyl transfer on the formation 
      of a water channel in SET8 is in accord with our previous reports on product 
      specificity by histone lysine monomethyltransferase SET7/9, large subunit lysine 
      dimethyltransferase (LSMT), and viral histone lysine trimethyltransferase (vSET). 
      The average value of the experimental DeltaG(E)() for the six lysine methyl 
      transfer reactions catalyzed by vSET, LSMT, and SET7/9 with p53 as a substrate is 
      22.1 +/- 1.0 kcal/mol, and the computed average (DeltaG(C)()) is 22.2 +/- 0.8 
      kcal/mol. In this study, the computed free energy barrier of the methyl transfer 
      reaction [Lys20-NH(2) + (+)AdoMet --> Lys20-N(Me)H(2)(+) + AdoHcy] catalyzed by 
      SET8 is 20.8 kcal/mol. This is in agreement with the value of 20.6 kcal/mol 
      calculated from the experimental rate constant (0.43 +/- 0.02 min(-1)). Our 
      bond-order computations establish that the H4-K20 monomethylation in SET8 is a 
      concerted linear S(N)2 displacement reaction.
FAU - Zhang, Xiaodong
AU  - Zhang X
AD  - Department of Chemistry and Biochemistry, University of California, Santa 
      Barbara, California 93106, USA.
FAU - Bruice, Thomas C
AU  - Bruice TC
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Histones)
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - 979-92-0 (S-Adenosylhomocysteine)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.1.1.43 (KMT5A protein, human)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Catalysis
MH  - Histone-Lysine N-Methyltransferase/*chemistry/*metabolism
MH  - Histones/chemistry/metabolism
MH  - Humans
MH  - Kinetics
MH  - Lysine/chemistry/metabolism
MH  - Methylation
MH  - Models, Chemical
MH  - Models, Molecular
MH  - *Molecular Dynamics Simulation
MH  - Molecular Structure
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - *Quantum Theory
MH  - S-Adenosylhomocysteine/chemistry/metabolism
MH  - S-Adenosylmethionine/chemistry/metabolism
MH  - Static Electricity
MH  - Substrate Specificity
EDAT- 2008/06/03 09:00
MHDA- 2010/05/08 06:00
CRDT- 2008/06/03 09:00
PHST- 2008/06/03 09:00 [pubmed]
PHST- 2010/05/08 06:00 [medline]
PHST- 2008/06/03 09:00 [entrez]
AID - 10.1021/bi800244s [doi]
PST - ppublish
SO  - Biochemistry. 2008 Jun 24;47(25):6671-7. doi: 10.1021/bi800244s.