Acyl-carrier-protein S-acetyltransferase

 

Acyl Carrier Protein S-acetyltransferase is a transferase enzyme that catalyzes the first biosynthetic pathway for fatty acid synthase. It transfers the acyl moiety to the MAT domain, which is the starting part of the synthesis. Research on this enzyme gives new insights that will be valuable for the development of specific and efficient therapeutic strategies for diabetes and related diseases.

 

Reference Protein and Structure

Sequence
P19096 UniProt (1.1.1.100, 1.3.1.39, 2.3.1.38, 2.3.1.39, 2.3.1.41, 2.3.1.85, 3.1.2.14, 4.2.1.59) IPR014043 (Sequence Homologues) (PDB Homologues)
Biological species
Mus musculus (house mouse) Uniprot
PDB
5my0 - KS-MAT DI-DOMAIN OF MOUSE FAS WITH MALONYL-COA (2.94 Å) PDBe PDBsum 5my0
Catalytic CATH Domains
(see all for 5my0)
Click To Show Structure

Enzyme Reaction (EC:2.3.1.38)

acetyl-CoA(4-)
CHEBI:57288ChEBI
+
O-(pantetheine-4'-phosphoryl)serine(1-) residue
CHEBI:64479ChEBI
→
coenzyme A(4-)
CHEBI:57287ChEBI
+
O-(S-acetylpantetheine-4'-phosphoryl)serine(1-) residue
CHEBI:78446ChEBI
Alternative enzyme names: [ACP]acetyltransferase, [Acyl-carrier-protein]acetyltransferase, Acetyl coenzyme A-acyl-carrier-protein transacylase, ACAT, ACP acetyltransferase, Acyl-carrier-protein acetyltransferase, [ACP]-acetyltransferase, [Acyl-carrier protein]-acetyltransferase,

Enzyme Mechanism

Introduction

Ping-pong catalytic mechanism: [acyl-carrier-protein] S-acetyltransferase catalyses the start of the biosynthetic pathway of fatty acid synthesis. During this reversible reaction, acylation of the MAT domain is followed by the transfer of the acyl moiety from the MAT to the ACP domain. A Ser581-His683 dyad plays a central role in this catalytic mechanism while Met499 and Leu582 stabilise the intermediates of the reaction by forming an oxyanion hole.

Catalytic Residues Roles

UniProt PDB* (5my0)
Met499 (main-N), Leu582 (main-N) Met499C (main-N), Leu582C (main-N) Form oxyanion hole that stabilize the tetrahedral intermediates formed during the reaction. transition state stabiliser
His683, Ser581 His683C, Ser581C Ser581-His683 dyad form the catalytic residues of the enzyme where the ping pong catalytic mechanism happen. activator, proton acceptor, 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, bimolecular nucleophilic addition, unimolecular elimination by the conjugate base, bimolecular nucleophilic substitution

References

  1. Paiva P et al. (2019), ChemCatChem, 11, 3853-3864. Human Fatty Acid Synthase: A Computational Study of the Transfer of the Acyl Moieties from MAT to the ACP Domain. DOI:10.1002/cctc.201900548.
  2. Milligan JC et al. (2019), Nat Chem Biol, 15, 669-671. Molecular basis for interactions between an acyl carrier protein and a ketosynthase. DOI:10.1038/s41589-019-0301-y. PMID:31209348.
  3. Paiva P et al. (2018), ACS Catal, 8, 4860-4872. Understanding the Catalytic Machinery and the Reaction Pathway of the Malonyl-Acetyl Transferase Domain of Human Fatty Acid Synthase. DOI:10.1021/acscatal.8b00577.

Step 1. His683 deprotonates Serine 581 and, the catalytic serine581 attacks the labile thioester bond of the acyl-CoA substrate

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His683C proton acceptor
Ser581C nucleophile
Met499C (main-N) transition state stabiliser
Leu582C (main-N) transition state stabiliser
His683C activator

Chemical Components

proton transfer, ingold: bimolecular nucleophilic addition

Step 2. The tetrahedral intermediate breaks down and deprotonates His683, and the CoA molecule is released from the active site. Met499 and Leu582 form oxyanion hole for the stabilization of transition-states and reaction intermediates.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His683C proton donor
Met499C (main-N) transition state stabiliser
Leu582C (main-N) transition state stabiliser

Chemical Components

ingold: unimolecular elimination by the conjugate base

Step 3. His683 deprotonates the thiol group which in turn attacks the ester carbonyl of the PNS arm of ACP.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His683C proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution

Step 4. A tetrahedral intermediate is postulated to be formed and probably subsequently resolved through the re-protonation of the catalytic serine by the conserved histidine residue. The acyl-ACP product is then released from the active site.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Ser581C proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution
Download: Image, Marvin File

Step 1. His683 deprotonates Serine 581 and, the catalytic serine581 attacks the labile thioester bond of the acyl-CoA substrate

Step 2. The tetrahedral intermediate breaks down and deprotonates His683, and the CoA molecule is released from the active site. Met499 and Leu582 form oxyanion hole for the stabilization of transition-states and reaction intermediates.

Step 3. His683 deprotonates the thiol group which in turn attacks the ester carbonyl of the PNS arm of ACP.

Step 4. A tetrahedral intermediate is postulated to be formed and probably subsequently resolved through the re-protonation of the catalytic serine by the conserved histidine residue. The acyl-ACP product is then released from the active site.

Products.

Contributors

Yordanos Abeje, Trung Nguyen, Antonio Ribeiro