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 Citations (Scopus)

Abstract

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
Volume89
Issue number17
StatePublished - 1992

Fingerprint

Prenylation
Phenylalanine
Cysteine
varespladib methyl
Peptides
Cholic Acid
Amino Acids
Brain
Enzymes
Methionine
Serine
Fatty Acids
p21(ras) farnesyl-protein transferase

Keywords

  • Covalent modification
  • p21 proteins
  • Protein prenylation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{925e2f084f3c4d78a750c228b5c6c05e,
title = "Tetrapeptide inhibitors of protein farnesyltransferase: Ammo-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation",
abstract = "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.",
keywords = "Covalent modification, p21 proteins, Protein prenylation",
author = "Brown, {Michael S.} and Goldstein, {Joseph L.} and Paris, {Kenneth J.} and Burnier, {John P.} and Marsters, {James C.}",
year = "1992",
language = "English (US)",
volume = "89",
pages = "8313--8316",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "17",

}

TY - JOUR

T1 - Tetrapeptide inhibitors of protein farnesyltransferase

T2 - Ammo-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation

AU - Brown, Michael S.

AU - Goldstein, Joseph L.

AU - Paris, Kenneth J.

AU - Burnier, John P.

AU - Marsters, James C.

PY - 1992

Y1 - 1992

N2 - 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.

AB - 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.

KW - Covalent modification

KW - p21 proteins

KW - Protein prenylation

UR - http://www.scopus.com/inward/record.url?scp=0026667497&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026667497&partnerID=8YFLogxK

M3 - Article

C2 - 1518863

AN - SCOPUS:0026667497

VL - 89

SP - 8313

EP - 8316

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

ER -