Histone acetyltransferase (crotonase type)

 

A member of the crotonase superfamily. Histone acetyltransferase catalyses the acetylation of N-terminal lysine residues in histones, as part of the displacement of histones by transition proteins and protamines during vertebrate spermatogenesis.

 

Reference Protein and Structure

Sequence
Q9Y232 UniProt (4.2.1.-) IPR001753 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
2gtr - Human chromodomain Y-like protein (1.9 Å) PDBe PDBsum 2gtr
Catalytic CATH Domains
3.90.226.10 CATHdb (see all for 2gtr)
Click To Show Structure

Enzyme Reaction (EC:2.3.1.48)

acetyl-CoA(4-)
CHEBI:57288ChEBI
+
L-lysinium residue
CHEBI:29969ChEBI
→
coenzyme A(4-)
CHEBI:57287ChEBI
+
N(6)-acetyl-L-lysine residue
CHEBI:61930ChEBI
+
hydron
CHEBI:15378ChEBI
Alternative enzyme names: Histone acetokinase, Histone acetylase, Histone transacetylase, Nucleosome-histone acetyltransferase, Lysine acetyltransferase, Protein lysine acetyltransferase, Acetyl-CoA:histone acetyltransferase,

Enzyme Mechanism

Introduction

Asp146 actiavtes the histone lysine by abstracting a proton from the Neta group. The lysine then attacks the carbonyl group of acetyl-CoA, with the negatively charged intermediate formed stabilises by the backbone amides of Leu66 and Leu115. The oxyanion then collapses, eliminating CoA with concomitant deprotonation of Asp146.

Catalytic Residues Roles

UniProt PDB* (2gtr)
Asp483 Asp146A Acts as a general acid/base. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Leu403 (main-N), Leu452 (main-N) Leu66A (main-N), Leu115A (main-N) Form the oxyanion hole that stabilises the negatively charged intermediates formed. hydrogen bond donor, electrostatic stabiliser
*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, bimolecular nucleophilic addition, overall reactant used, intermediate formation, unimolecular elimination by the conjugate base, intermediate terminated, overall product formed, native state of enzyme regenerated

References

  1. Lahn BT et al. (2002), Proc Natl Acad Sci U S A, 99, 8707-8712. Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis. DOI:10.1073/pnas.082248899. PMID:12072557.

Step 1. Asp146 abstracts a proton from the NE group of lysine in histones, with the concomitant attack of the amino group to C1 in the substrate. This is facilitated by the binding of the thioester oxygen atom to an oxyanion hole formed by the peptide nitrogens of Leu66 and of Leu115.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Leu115A (main-N) electrostatic stabiliser, hydrogen bond donor
Leu66A (main-N) electrostatic stabiliser, hydrogen bond donor
Asp146A hydrogen bond acceptor
Asp146A proton acceptor

Chemical Components

proton transfer, ingold: bimolecular nucleophilic addition, overall reactant used, intermediate formation

Step 2. The oxyanion intermediate collapses to give two products with the help of a proton donated by Asp146

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Leu115A (main-N) hydrogen bond donor, electrostatic stabiliser
Asp146A hydrogen bond donor
Leu66A (main-N) hydrogen bond donor, electrostatic stabiliser
Asp146A proton donor

Chemical Components

ingold: unimolecular elimination by the conjugate base, proton transfer, intermediate terminated, overall product formed, native state of enzyme regenerated
Download: Image, Marvin File

Step 1. Asp146 abstracts a proton from the NE group of lysine in histones, with the concomitant attack of the amino group to C1 in the substrate. This is facilitated by the binding of the thioester oxygen atom to an oxyanion hole formed by the peptide nitrogens of Leu66 and of Leu115.

Step 2. The oxyanion intermediate collapses to give two products with the help of a proton donated by Asp146

Products.

Contributors

Daniel E. Almonacid, Sophie T. Williams, Gemma L. Holliday