An inhibitor of protein arginine methyltransferases, 7,7′- carbonylbis(azanediyl)bis4-hydroxynaphthalene-2-sulfonic acid (AMI-1), is a potent scavenger of NADPH-oxidase-derived superoxide

Feng Chen, David J Fulton

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7′-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6- tetramethylpiperydine-1-oxyl (Tempol).

Original languageEnglish (US)
Pages (from-to)280-287
Number of pages8
JournalMolecular Pharmacology
Volume77
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Protein-Arginine N-Methyltransferases
Sulfonic Acids
NADPH Oxidase
Superoxides
Methylation
Proteins
Reactive Oxygen Species
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
2-naphthol
Nucleic Acids
Carrier Proteins
Cardiovascular Diseases
Antioxidants

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

@article{e2e2b2ea9668413ea390543957bd5fe4,
title = "An inhibitor of protein arginine methyltransferases, 7,7′- carbonylbis(azanediyl)bis4-hydroxynaphthalene-2-sulfonic acid (AMI-1), is a potent scavenger of NADPH-oxidase-derived superoxide",
abstract = "The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7′-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6- tetramethylpiperydine-1-oxyl (Tempol).",
author = "Feng Chen and Fulton, {David J}",
year = "2010",
month = "2",
day = "1",
doi = "10.1124/mol.109.061077",
language = "English (US)",
volume = "77",
pages = "280--287",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - An inhibitor of protein arginine methyltransferases, 7,7′- carbonylbis(azanediyl)bis4-hydroxynaphthalene-2-sulfonic acid (AMI-1), is a potent scavenger of NADPH-oxidase-derived superoxide

AU - Chen, Feng

AU - Fulton, David J

PY - 2010/2/1

Y1 - 2010/2/1

N2 - The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7′-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6- tetramethylpiperydine-1-oxyl (Tempol).

AB - The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7′-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6- tetramethylpiperydine-1-oxyl (Tempol).

UR - http://www.scopus.com/inward/record.url?scp=74549155206&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74549155206&partnerID=8YFLogxK

U2 - 10.1124/mol.109.061077

DO - 10.1124/mol.109.061077

M3 - Article

C2 - 19903831

AN - SCOPUS:74549155206

VL - 77

SP - 280

EP - 287

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -