Estrone sulfotransferase

 

Estrogen sulfotransferase (EST) transfers the sulfate group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the phenolic oxygen of estrogenic steroids. EST plays a role in many carcinogenic processes, with polymorphism implicated in genetic risk towards some cancers.

 

Reference Protein and Structure

Sequence
P49888 UniProt (2.8.2.4) IPR000863 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1hy3 - CRYSTAL STRUCTURE OF HUMAN ESTROGEN SULFOTRANSFERASE V269E MUTANT IN THE PRESENCE OF PAPS (1.8 Å) PDBe PDBsum 1hy3
Catalytic CATH Domains
3.40.50.300 CATHdb (see all for 1hy3)
Click To Show Structure

Enzyme Reaction (EC:2.8.2.4)

estrone
CHEBI:17263ChEBI
+
3'-phosphonato-5'-adenylyl sulfate(4-)
CHEBI:58339ChEBI
→
estrone 3-sulfate
CHEBI:17474ChEBI
+
adenosine 3',5'-bismonophosphate(4-)
CHEBI:58343ChEBI
Alternative enzyme names: 3'-phosphoadenylyl sulfate-estrone 3-sulfotransferase, 3'-phosphoadenylylsulfate:oestrone sulfotransferase, Estrogen sulfotransferase, Estrogen sulphotransferase,

Enzyme Mechanism

Introduction

The mechanism is an SN2-like in-line displacement, with the phenolic hydroxy group acting as the nucleophile (made more nucleophilic by hydrogen bonding with His 107, which also transfers the phenolic proton to the sulfate group).

Lys 47 hydrogen bonds to the oxygen atom bridging PAPS 5' phosphate and sulfate groups. This promotes dissociation of the sulfate group from PAPS and may transfer a proton to the PAP product. The invariant Ser 137 plays an important regulatory role. It hydrogen bonds to Lys 47 in the absence of the steroid substrate, preventing Lys 47 assisting in hydrolysis of PAPS. Once the steroid binds, the hydrogen bond is broken and the transfer reaction can take place.

Catalytic Residues Roles

UniProt PDB* (1hy3)
Lys47 Lys47A This residue promotes dissociation of the sulfate group from PAPS and the transfer to the steroid. It also stabilises the transition state and may also donate a proton to the PAP product hydrogen bond donor, electrostatic stabiliser
His107 His107A This residue activates the phenolic hydroxy group of the steroid substrate as a nucleophile. It also transfers the hydrogen bonded proton from the phenolic oxygen to the sulfate group. proton relay, hydrogen bond acceptor, proton acceptor, proton donor
Ser137 Ser137A Plays an important regulatory role. Hydrogen bonds to Lys 47 in the absence of the steroid substrate, preventing Lys 47 assisting in hydrolysis of PAPS. Once the steroid binds, the hydrogen bond is broken and the transfer reaction can take place. hydrogen bond acceptor, steric role
*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

bimolecular nucleophilic substitution, proton transfer, overall reactant used, overall product formed, native state of enzyme regenerated

References

  1. Pedersen LC et al. (2002), J Biol Chem, 277, 17928-17932. Crystal Structure of the Human Estrogen Sulfotransferase-PAPS Complex: EVIDENCE FOR CATALYTIC ROLE OF Ser137 IN THE SULFURYL TRANSFER REACTION. DOI:10.1074/jbc.m111651200. PMID:11884392.
  2. Chapman E et al. (2004), Angew Chem Int Ed Engl, 43, 3526-3548. Sulfotransferases: structure, mechanism, biological activity, inhibition, and synthetic utility. DOI:10.1002/anie.200300631. PMID:15293241.

Step 1. The sulfate of 3'-phosphoadenylyl sulfate attacks the alcohol group of estrone, which then attacks the sulfate in a nucleophilic substitution. The transition state of this reaction involves a strong hydrogen bond between the His107 and estrone, which effectively results in a proton relay.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His107A hydrogen bond acceptor, proton relay
Ser137A hydrogen bond acceptor, steric role
Lys47A hydrogen bond donor, electrostatic stabiliser
His107A proton donor, proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution, proton transfer, overall reactant used, overall product formed, native state of enzyme regenerated
Download: Image, Marvin File

Step 1. The sulfate of 3'-phosphoadenylyl sulfate attacks the alcohol group of estrone, which then attacks the sulfate in a nucleophilic substitution. The transition state of this reaction involves a strong hydrogen bond between the His107 and estrone, which effectively results in a proton relay.

Products.

Contributors

Gemma L. Holliday, Daniel E. Almonacid, Jonathan T. W. Ng, James Torrance, Charity Hornby