title: Farnesylcysteine analogues inhibit chemotactic peptide receptor-mediated G-protein activation in human HL-60 granulocyte membranes.
abstract: Analogues of S-prenylated cysteine like N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC) have previously been shown to inhibit the carboxyl methylation of proteins carrying a C-terminal S-prenylated cysteine residue and to block the endotoxin-activated serum-elicited chemotactic response of mouse macrophages. Here, we show that AFC inhibits both basal and formyl peptide receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) to and hydrolysis of GTP by membranes of myeloid differentiated HL-60 granulocytes. Receptor-stimulated GTP[S] binding and GTP hydrolysis are more sensitive to AFC inhibition than basal G-protein functions. Inhibition of formyl peptide receptor-mediated G-protein activation is also observed for S-trans,trans-farnesyl-3-thiopropionic acid, but not for N-acetyl-S-trans-geranyl-L-cysteine, N-acetyl-L-cysteine, or the methyl ester of AFC, suggesting that the farnesyl moiety and the carboxyl group, but not the peptide bond of AFC are required for inhibition. The observations that exogeneous S-adenosyl-L-methionine is apparently not required for and S-adenosyl-L-homocysteine does not attenuate the inhibitory action of AFC raise the distinct possibility that AFC inhibits receptor-mediated G-protein interaction by a mechanism other than inhibition of protein carboxyl methylation.
authors.affiliation: Molecular Pharmacology Division, German Cancer Research Center, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Scheer
authors.forename: P
authors.initials: P
authors.lastname: Gierschik
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009240:N-Formylmethionine Leucyl-Phenylalanine; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C068268:N-acetyl-S-farnesylcysteine; D000111:Acetylcysteine