Small molecule regulators of protein arginine methyltransferases

J Biol Chem. 2004 Jun 4;279(23):23892-9. doi: 10.1074/jbc.M401853200. Epub 2004 Mar 31.

Abstract

Here we report the identification of small molecules that specifically inhibit protein arginine N-methyltransferase (PRMT) activity. PRMTs are a family of proteins that either monomethylate or dimethylate the guanidino nitrogen atoms of arginine side chains. This common post-translational modification is implicated in protein trafficking, signal transduction, and transcriptional regulation. Most methyltransferases use the methyl donor, S-adenosyl-L-methionine (AdoMet), as a cofactor. Current methyltransferase inhibitors display limited specificity, indiscriminately targeting all enzymes that use AdoMet. In this screen we have identified a primary compound, AMI-1, that specifically inhibits arginine, but not lysine, methyltransferase activity in vitro and does not compete for the AdoMet binding site. Furthermore, AMI-1 prevents in vivo arginine methylation of cellular proteins and can modulate nuclear receptor-regulated transcription from estrogen and androgen response elements, thus operating as a brake on certain hormone actions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arginine / chemistry
  • Binding Sites
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • DNA Methylation
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • Green Fluorescent Proteins
  • Humans
  • Inhibitory Concentration 50
  • Light
  • Luciferases / metabolism
  • Luminescent Proteins / metabolism
  • Lysine / chemistry
  • Methylation
  • Models, Chemical
  • Nitrogen / chemistry
  • Plasmids / metabolism
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Protein Transport
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / chemistry
  • S-Adenosylmethionine / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Ultraviolet Rays

Substances

  • Epitopes
  • Luminescent Proteins
  • Green Fluorescent Proteins
  • S-Adenosylmethionine
  • Arginine
  • Luciferases
  • Protein-Arginine N-Methyltransferases
  • Glutathione Transferase
  • Lysine
  • Nitrogen