Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase

Joseph L. Goldstein, Michael S. Brown, Sarah J. Stradley, Yuval Reiss, Lila M. Gierasch

Research output: Contribution to journalArticle

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Abstract

The protein farnesyltransferase from rat brain was previously shown to be inhibited competitively by tetrapeptides that conform to the consensus Cys-A1-A2-X, where A1 and A2 are aliphatic amino acids and X is methionine, serine, or phenylalanine. In the current studies we use a thin layer chromatography assay to show that most of these tetrapeptides are themselves farnesylated by the purified enzyme. Two classes of tetrapeptides are not farnesylated and therefore act as true inhibitors: 1) those that contain an aromatic residue at the A2 position and 2) those that contain penicillamine (β,β-dimethylcysteine) in place of cysteine. The most potent of these pure inhibitors was Cys-Val-Phe-Met, which inhibited farnesyltransferase activity by 50% at <0.1 μM. These data indicate that the inclusion of bulky aromatic or methyl residues in a tetrapeptide can abolish prenyl group transfer without blocking binding to the enzyme. This information should be useful in the design of peptides or peptidomimetics that inhibit farnesylation and thus block the action of p21ras proteins in animal cells.

Original languageEnglish (US)
Pages (from-to)15575-15578
Number of pages4
JournalJournal of Biological Chemistry
Volume266
Issue number24
StatePublished - 1991

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Penicillamine
varespladib methyl
Farnesyltranstransferase
Peptidomimetics
Thin layer chromatography
Enzymes
Phenylalanine
Methionine
Serine
Prenylation
Cysteine
Rats
Assays
Brain
Animals
Cells
Thin Layer Chromatography
Amino Acids
Peptides
Fatty Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. / Goldstein, Joseph L.; Brown, Michael S.; Stradley, Sarah J.; Reiss, Yuval; Gierasch, Lila M.

In: Journal of Biological Chemistry, Vol. 266, No. 24, 1991, p. 15575-15578.

Research output: Contribution to journalArticle

Goldstein, JL, Brown, MS, Stradley, SJ, Reiss, Y & Gierasch, LM 1991, 'Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase', Journal of Biological Chemistry, vol. 266, no. 24, pp. 15575-15578.
Goldstein, Joseph L. ; Brown, Michael S. ; Stradley, Sarah J. ; Reiss, Yuval ; Gierasch, Lila M. / Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. In: Journal of Biological Chemistry. 1991 ; Vol. 266, No. 24. pp. 15575-15578.
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