Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics

Meenakshi Nigam, Churl Min Seong, Yimin Qian, Andrew Hamilton, Said M. Sebti

Research output: Contribution to journalArticle

Abstract

The ras oncogene product p21ras requires farnesylation and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by p21ras farnesyltransferase, which transfers farnesyl from farnesylpyrophosphate to the cysteine of the CA1A2X carboxyl-terminal tetrapeptide of p21ras. In the present report, we describe potent inhibition of p21ras farnesyltransferase by CA1A2X peptidomimetics containing no peptidic amide bonds. We synthesized a series of CA1A2X analogues where the 2 aliphatic amino acids A1 and A2 were replaced by a hydrophobic spacer, 3-aminomethylbenzoic acid (AMBA). The peptidomimetic Cys-AMBA-Met, inhibits p21ras farnesyltransferase from human colon carcinoma (COLO-205) and Burkitt's lymphoma (Daudi) with IC50 values of 60 and 120 nM, respectively. Cys-AMBA-Met is 3-, 8-, and 9-fold (COLO-205) and 2-, 5-, and 7-fold (Daudi) more potent than the corresponding tetrapeptides of p21KB-ras (CVIM), p21N-ras (CVVM), and p21KA-ras (CIIM), respectively. Replacing methionine at the X position with negatively charged glutamate reduces its ability to inhibit the enzyme, whereas positively charged lysine at this position abolishes the inhibitory character of the peptidomimetic. A hydrophobic moiety at the X position, as in Cys-AMBA-Phe, retains potent inhibitory activity. Leucine in the X position of CA1A2X is a post-translational signal for protein geranylgeranylation rather than farnesylation, and, as expected, Cys-AMBA-Leu does not inhibit the enzyme. Furthermore, CVIM, CVVM, and CIIM are farnesylated by human p21ras farnesyltransferases and inhibit these enzymes by serving as alternative substrates. In contrast, the peptidomimetics described here are true p21ras farnesyltransferase inhibitors since none is farnesylated by this enzyme.

Original languageEnglish (US)
Pages (from-to)20695-20698
Number of pages4
JournalJournal of Biological Chemistry
Volume268
Issue number28
StatePublished - Oct 5 1993

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Farnesyltranstransferase
Peptidomimetics
Tumors
Acids
Prenylation
Enzymes
Neoplasms
Protein Prenylation
Burkitt Lymphoma
ras Genes
Oncogene Proteins
Cell membranes
Post Translational Protein Processing
varespladib methyl
Amides
Leucine
Methionine
Inhibitory Concentration 50
Lysine
Cysteine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics. / Nigam, Meenakshi; Seong, Churl Min; Qian, Yimin; Hamilton, Andrew; Sebti, Said M.

In: Journal of Biological Chemistry, Vol. 268, No. 28, 05.10.1993, p. 20695-20698.

Research output: Contribution to journalArticle

Nigam, Meenakshi ; Seong, Churl Min ; Qian, Yimin ; Hamilton, Andrew ; Sebti, Said M. / Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 28. pp. 20695-20698.
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abstract = "The ras oncogene product p21ras requires farnesylation and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by p21ras farnesyltransferase, which transfers farnesyl from farnesylpyrophosphate to the cysteine of the CA1A2X carboxyl-terminal tetrapeptide of p21ras. In the present report, we describe potent inhibition of p21ras farnesyltransferase by CA1A2X peptidomimetics containing no peptidic amide bonds. We synthesized a series of CA1A2X analogues where the 2 aliphatic amino acids A1 and A2 were replaced by a hydrophobic spacer, 3-aminomethylbenzoic acid (AMBA). The peptidomimetic Cys-AMBA-Met, inhibits p21ras farnesyltransferase from human colon carcinoma (COLO-205) and Burkitt's lymphoma (Daudi) with IC50 values of 60 and 120 nM, respectively. Cys-AMBA-Met is 3-, 8-, and 9-fold (COLO-205) and 2-, 5-, and 7-fold (Daudi) more potent than the corresponding tetrapeptides of p21KB-ras (CVIM), p21N-ras (CVVM), and p21KA-ras (CIIM), respectively. Replacing methionine at the X position with negatively charged glutamate reduces its ability to inhibit the enzyme, whereas positively charged lysine at this position abolishes the inhibitory character of the peptidomimetic. A hydrophobic moiety at the X position, as in Cys-AMBA-Phe, retains potent inhibitory activity. Leucine in the X position of CA1A2X is a post-translational signal for protein geranylgeranylation rather than farnesylation, and, as expected, Cys-AMBA-Leu does not inhibit the enzyme. Furthermore, CVIM, CVVM, and CIIM are farnesylated by human p21ras farnesyltransferases and inhibit these enzymes by serving as alternative substrates. In contrast, the peptidomimetics described here are true p21ras farnesyltransferase inhibitors since none is farnesylated by this enzyme.",
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T1 - Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics

AU - Nigam, Meenakshi

AU - Seong, Churl Min

AU - Qian, Yimin

AU - Hamilton, Andrew

AU - Sebti, Said M.

PY - 1993/10/5

Y1 - 1993/10/5

N2 - The ras oncogene product p21ras requires farnesylation and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by p21ras farnesyltransferase, which transfers farnesyl from farnesylpyrophosphate to the cysteine of the CA1A2X carboxyl-terminal tetrapeptide of p21ras. In the present report, we describe potent inhibition of p21ras farnesyltransferase by CA1A2X peptidomimetics containing no peptidic amide bonds. We synthesized a series of CA1A2X analogues where the 2 aliphatic amino acids A1 and A2 were replaced by a hydrophobic spacer, 3-aminomethylbenzoic acid (AMBA). The peptidomimetic Cys-AMBA-Met, inhibits p21ras farnesyltransferase from human colon carcinoma (COLO-205) and Burkitt's lymphoma (Daudi) with IC50 values of 60 and 120 nM, respectively. Cys-AMBA-Met is 3-, 8-, and 9-fold (COLO-205) and 2-, 5-, and 7-fold (Daudi) more potent than the corresponding tetrapeptides of p21KB-ras (CVIM), p21N-ras (CVVM), and p21KA-ras (CIIM), respectively. Replacing methionine at the X position with negatively charged glutamate reduces its ability to inhibit the enzyme, whereas positively charged lysine at this position abolishes the inhibitory character of the peptidomimetic. A hydrophobic moiety at the X position, as in Cys-AMBA-Phe, retains potent inhibitory activity. Leucine in the X position of CA1A2X is a post-translational signal for protein geranylgeranylation rather than farnesylation, and, as expected, Cys-AMBA-Leu does not inhibit the enzyme. Furthermore, CVIM, CVVM, and CIIM are farnesylated by human p21ras farnesyltransferases and inhibit these enzymes by serving as alternative substrates. In contrast, the peptidomimetics described here are true p21ras farnesyltransferase inhibitors since none is farnesylated by this enzyme.

AB - The ras oncogene product p21ras requires farnesylation and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by p21ras farnesyltransferase, which transfers farnesyl from farnesylpyrophosphate to the cysteine of the CA1A2X carboxyl-terminal tetrapeptide of p21ras. In the present report, we describe potent inhibition of p21ras farnesyltransferase by CA1A2X peptidomimetics containing no peptidic amide bonds. We synthesized a series of CA1A2X analogues where the 2 aliphatic amino acids A1 and A2 were replaced by a hydrophobic spacer, 3-aminomethylbenzoic acid (AMBA). The peptidomimetic Cys-AMBA-Met, inhibits p21ras farnesyltransferase from human colon carcinoma (COLO-205) and Burkitt's lymphoma (Daudi) with IC50 values of 60 and 120 nM, respectively. Cys-AMBA-Met is 3-, 8-, and 9-fold (COLO-205) and 2-, 5-, and 7-fold (Daudi) more potent than the corresponding tetrapeptides of p21KB-ras (CVIM), p21N-ras (CVVM), and p21KA-ras (CIIM), respectively. Replacing methionine at the X position with negatively charged glutamate reduces its ability to inhibit the enzyme, whereas positively charged lysine at this position abolishes the inhibitory character of the peptidomimetic. A hydrophobic moiety at the X position, as in Cys-AMBA-Phe, retains potent inhibitory activity. Leucine in the X position of CA1A2X is a post-translational signal for protein geranylgeranylation rather than farnesylation, and, as expected, Cys-AMBA-Leu does not inhibit the enzyme. Furthermore, CVIM, CVVM, and CIIM are farnesylated by human p21ras farnesyltransferases and inhibit these enzymes by serving as alternative substrates. In contrast, the peptidomimetics described here are true p21ras farnesyltransferase inhibitors since none is farnesylated by this enzyme.

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