Aralkyl selenoglycosides and related selenosugars in acetylated form activate protein phosphatase-1 and -2A

Zoltán Kónya, Bálint Bécsi, A. Kiss, István Tamás, Beáta Lontay, László Szilágyi, K. Kövér, F. Erdődi

Research output: Contribution to journalArticle

Abstract

Aralkyl and aryl selenoglycosides as well as glycosyl selenocarboxylate derivatives were assayed on the activity of protein phosphatase-1 (PP1) and -2A (PP2A) catalytic subunits (PP1c and PP2Ac) in search of compounds for PP1c and PP2Ac effectors. The majority of tested selenoglycosides activated both PP1c and PP2Ac by ∼2–4-fold in a phosphatase assay with phosphorylated myosin light chain substrate when the hydroxyl groups of the glycosyl moiety were acetylated, but they were without any effects in the non-acetylated forms. A peptide from the myosin phosphatase target subunit-1 (MYPT123–38) that included an RVxF PP1c-binding motif attenuated activation of PP1c by 2-Trifluoromethylbenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (TFM-BASG) and 4-Bromobenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (Br-BASG). MYPT123–38 stimulated PP2Ac and contributed to PP2Ac activation exerted by either Br-BASG or TFM-BASG. Br-BASG and TFM-BASG suppressed partially binding of PP1c to MYPT1 in surface plasmon resonance based binding experiments. Molecular docking predicted that the hydrophobic binding surfaces in PP1c for interaction with either the RVxF residues of PP1c-interactors or selenoglycosides are partially overlapped. Br-BASG and TFM-BASG caused a moderate increase in the phosphatase activity of HeLa cells in 1 h, and suppressed cell viability in 24 h incubations. In conclusion, our present study identified selenoglycosides as novel activators of PP1 and PP2A as well as provided insights into the structural background of their interactions establishing a molecular model for future design of more efficient phosphatase activator molecules.

Original languageEnglish
Pages (from-to)1875-1884
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number8
DOIs
Publication statusPublished - May 1 2018

Fingerprint

Protein Phosphatase 1
Protein Phosphatase 2
Phosphoric Monoester Hydrolases
Chemical activation
Myosin-Light-Chain Phosphatase
Myosin Light Chains
Molecular Models
Surface Plasmon Resonance
Transcription Factor AP-1
Surface plasmon resonance
HeLa Cells
Hydroxyl Radical
Assays
Catalytic Domain
Cell Survival
Cells
Derivatives
Peptides
Molecules
Substrates

Keywords

  • HeLa cells
  • Molecular docking
  • Protein phosphatase-1
  • Protein phosphatase-2A
  • Selenoglycosides
  • Surface plasmon resonance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Aralkyl selenoglycosides and related selenosugars in acetylated form activate protein phosphatase-1 and -2A. / Kónya, Zoltán; Bécsi, Bálint; Kiss, A.; Tamás, István; Lontay, Beáta; Szilágyi, László; Kövér, K.; Erdődi, F.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 8, 01.05.2018, p. 1875-1884.

Research output: Contribution to journalArticle

Kónya, Zoltán ; Bécsi, Bálint ; Kiss, A. ; Tamás, István ; Lontay, Beáta ; Szilágyi, László ; Kövér, K. ; Erdődi, F. / Aralkyl selenoglycosides and related selenosugars in acetylated form activate protein phosphatase-1 and -2A. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 8. pp. 1875-1884.
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AU - Bécsi, Bálint

AU - Kiss, A.

AU - Tamás, István

AU - Lontay, Beáta

AU - Szilágyi, László

AU - Kövér, K.

AU - Erdődi, F.

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AB - Aralkyl and aryl selenoglycosides as well as glycosyl selenocarboxylate derivatives were assayed on the activity of protein phosphatase-1 (PP1) and -2A (PP2A) catalytic subunits (PP1c and PP2Ac) in search of compounds for PP1c and PP2Ac effectors. The majority of tested selenoglycosides activated both PP1c and PP2Ac by ∼2–4-fold in a phosphatase assay with phosphorylated myosin light chain substrate when the hydroxyl groups of the glycosyl moiety were acetylated, but they were without any effects in the non-acetylated forms. A peptide from the myosin phosphatase target subunit-1 (MYPT123–38) that included an RVxF PP1c-binding motif attenuated activation of PP1c by 2-Trifluoromethylbenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (TFM-BASG) and 4-Bromobenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (Br-BASG). MYPT123–38 stimulated PP2Ac and contributed to PP2Ac activation exerted by either Br-BASG or TFM-BASG. Br-BASG and TFM-BASG suppressed partially binding of PP1c to MYPT1 in surface plasmon resonance based binding experiments. Molecular docking predicted that the hydrophobic binding surfaces in PP1c for interaction with either the RVxF residues of PP1c-interactors or selenoglycosides are partially overlapped. Br-BASG and TFM-BASG caused a moderate increase in the phosphatase activity of HeLa cells in 1 h, and suppressed cell viability in 24 h incubations. In conclusion, our present study identified selenoglycosides as novel activators of PP1 and PP2A as well as provided insights into the structural background of their interactions establishing a molecular model for future design of more efficient phosphatase activator molecules.

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