Histone-lysine N-methyltransferase (Suvar3-9 subfamily)

 

Histone lysine methylation is part of the histone code that regulates chromatin function. Histone lysine methyltransferases (HKMT) differ both in their substrate specificity for the various acceptor lysines as well as in their product specificity for the number of methyl groups (one, two, or three) they transfer. Known targets for HKMT include Lys4, 9, 27, 36, and 79 in histone H3 and Lys20 in histone H4. DIM-5 of N. crassa generates primarily trimethyl Lys9, which marks chromatin regions for DNA methylation.

 

Reference Protein and Structure

Sequences
Q8X225 UniProt (2.1.1.355)
P61830 UniProt IPR001214 (Sequence Homologues) (PDB Homologues)
Biological species
Neurospora crassa OR74A (Fungus) Uniprot
PDB
1peg - Structural basis for the product specificity of histone lysine methyltransferases (2.59 Å) PDBe PDBsum 1peg
Catalytic CATH Domains
2.170.270.10 CATHdb (see all for 1peg)
Click To Show Structure

Enzyme Reaction (EC:2.1.1.43)

L-lysinium residue
CHEBI:29969ChEBI
+
S-adenosyl-L-methionine zwitterion
CHEBI:59789ChEBI
→
S-adenosyl-L-homocysteine zwitterion
CHEBI:57856ChEBI
+
N(6)-methyl-L-lysinium residue
CHEBI:61929ChEBI
+
hydron
CHEBI:15378ChEBI
Alternative enzyme names: Histone H1-specific S-adenosylmethionine:protein-lysine N-methyltransferase, Protein (lysine) methyltransferase, Protein methylase 3, Protein methylase III, Protein methyltransferase II, Protein-lysine N-methyltransferase, S-adenosyl-L-methionine:histone-L-lysine 6-N-methyltransferase,

Enzyme Mechanism

Introduction

At the optimum pH the catalytic Tyr178 is deprotonated and so able to act as a general base, abstracting a proton from the target lysine in the first round of methylation (or target methyl/dimethyl lysine in subsequent rounds). The lysine may then perform a direct nucleophilic attack on the S=adenosyl-L-methionine (SAM) methyl group. Methyl lysine is formed which, in the case of N. crassa DIM-5, generally remains in the active site while the used cofactor S-adenosyl homocystine (SAH) is exchanged for new SAM.

Catalytic Residues Roles

UniProt PDB* (1peg)
Tyr296 Tyr283(267)A Electrostatic interation with the sulfur on SAM acts to stabilise the charged cofactor. electrostatic stabiliser
Tyr191 Tyr178(162)A Abstracts a proton from the amine group of the lysine side chain. proton acceptor, activator, electrostatic stabiliser, proton donor
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

proton transfer, overall reactant used, intramolecular nucleophilic substitution, overall product formed, native state of enzyme regenerated, inferred reaction step

References

  1. Zhang X et al. (2003), Mol Cell, 12, 177-185. Structural basis for the product specificity of histone lysine methyltransferases. DOI:10.2210/pdb1peg/pdb. PMID:12887903.

Step 1. Tyr178 deprotonates the amine group of the lysine side chain.

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Catalytic Residues Roles

Residue Roles
Tyr283(267)A electrostatic stabiliser
Tyr178(162)A activator, proton acceptor

Chemical Components

proton transfer, overall reactant used

Step 2. In an SN2 reaction the amine group of the lysine residue attacks the methyl of SAM, forming the secondary amine product and SAH.

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Catalytic Residues Roles

Residue Roles
Tyr178(162)A electrostatic stabiliser
Tyr283(267)A electrostatic stabiliser

Chemical Components

ingold: intramolecular nucleophilic substitution, overall product formed

Step 3. In an inferred reaction step Tyr178 is deprotonated to regenerate the native state of the enzyme.

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Catalytic Residues Roles

Residue Roles
Tyr178(162)A proton donor

Chemical Components

proton transfer, native state of enzyme regenerated, inferred reaction step
Download: Image, Marvin File

Step 1. Tyr178 deprotonates the amine group of the lysine side chain.

Step 2. In an SN2 reaction the amine group of the lysine residue attacks the methyl of SAM, forming the secondary amine product and SAH.

Step 3. In an inferred reaction step Tyr178 is deprotonated to regenerate the native state of the enzyme.

Products.

Contributors

Gemma L. Holliday, Amelia Brasnett