Tetrapeptide inhibitors of protein farnesyltransferase: Ammo-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation

Michael S. Brown, Joseph L. Goldstein, Kenneth J. Paris, John P. Burnier, James C. Marsters

Research output: Contribution to journalArticle

74 Scopus citations


Protein farnesyltransferase from rat brain transfers farnesyl residues to cysteine residues in tetrapeptides that conform to the sequence CA1A2X, where C is cysteine, A1 and A2 are aliphatic amino acids, and X is methionine or serine. When the A2 residue is aromatic [e.g., phenylalanine as in Cys-Val-Phe-Met (CVFM)], the tetrapeptide continues to bind to the enzyme, but it can no longer accept a farnesyl group, and it becomes a pure inhibitor. The current studies show that this resistance to farnesylation also requires a positive charge on the cysteine amino group. Derivatization of this group with acetyl, octanoyl, or cholic acid residues or extension of the peptide with an additional amino acid restores the ability of phenylalaninecontaining peptides to accept a farnesyl residue. The same result was obtained when the amino group of cysteine was deleted (mercaptopropionyl-VFM). These data suggest that the positive change on the cysteine amino group acts in concert with an aromatic residue in the A2 position to render peptides resistant to farnesylation by the rat brain enzyme.

Original languageEnglish (US)
Pages (from-to)8313-8316
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Jan 1 1992



  • Covalent modification
  • Protein prenylation
  • p21 proteins

ASJC Scopus subject areas

  • General

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