Structural rearrangement of SULT2A1

Effects on dehydroepiandrosterone and raloxifene sulfation

Ian T. Cook, Thomas S. Leyh, Thomas S. Leyh, Charles N. Falany

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3′,5′-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. Materials and methods: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. Results: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. Conclusions: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.

Original languageEnglish (US)
Pages (from-to)81-87
Number of pages7
JournalHormone Molecular Biology and Clinical Investigation
Volume1
Issue number2
DOIs
StatePublished - Jan 1 2010

Fingerprint

Dehydroepiandrosterone
Phosphoadenosine Phosphosulfate
Sulfates
Raloxifene Hydrochloride
Sulfotransferases
Molecular Models
Xenobiotics
Sterols
Hydroxyl Radical
Catalytic Domain
Protein Isoforms
Peptides

Keywords

  • Dehydroepiandrosterone
  • Drug metabolism
  • Molecular modeling
  • Raloxifene
  • Sulfation
  • Sulfotransferase
  • SULT2A1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)
  • Molecular Biology
  • Endocrinology

Cite this

Structural rearrangement of SULT2A1 : Effects on dehydroepiandrosterone and raloxifene sulfation. / Cook, Ian T.; Leyh, Thomas S.; Leyh, Thomas S.; Falany, Charles N.

In: Hormone Molecular Biology and Clinical Investigation, Vol. 1, No. 2, 01.01.2010, p. 81-87.

Research output: Contribution to journalArticle

@article{78437eea2df54092a8070ffa95bf1af1,
title = "Structural rearrangement of SULT2A1: Effects on dehydroepiandrosterone and raloxifene sulfation",
abstract = "Background: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3′,5′-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. Materials and methods: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. Results: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. Conclusions: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.",
keywords = "Dehydroepiandrosterone, Drug metabolism, Molecular modeling, Raloxifene, Sulfation, Sulfotransferase, SULT2A1",
author = "Cook, {Ian T.} and Leyh, {Thomas S.} and Leyh, {Thomas S.} and Falany, {Charles N.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1515/HMBCI.2010.012",
language = "English (US)",
volume = "1",
pages = "81--87",
journal = "Hormone Molecular Biology and Clinical Investigation",
issn = "1868-1883",
publisher = "Walter de Gruyter GmbH",
number = "2",

}

TY - JOUR

T1 - Structural rearrangement of SULT2A1

T2 - Effects on dehydroepiandrosterone and raloxifene sulfation

AU - Cook, Ian T.

AU - Leyh, Thomas S.

AU - Leyh, Thomas S.

AU - Falany, Charles N.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Background: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3′,5′-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. Materials and methods: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. Results: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. Conclusions: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.

AB - Background: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3′,5′-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. Materials and methods: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. Results: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. Conclusions: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.

KW - Dehydroepiandrosterone

KW - Drug metabolism

KW - Molecular modeling

KW - Raloxifene

KW - Sulfation

KW - Sulfotransferase

KW - SULT2A1

UR - http://www.scopus.com/inward/record.url?scp=84886588118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886588118&partnerID=8YFLogxK

U2 - 10.1515/HMBCI.2010.012

DO - 10.1515/HMBCI.2010.012

M3 - Article

VL - 1

SP - 81

EP - 87

JO - Hormone Molecular Biology and Clinical Investigation

JF - Hormone Molecular Biology and Clinical Investigation

SN - 1868-1883

IS - 2

ER -