Advances in the development of farnesyltransferase inhibitors: substrate recognition by protein farnesyltransferase.
A variety of compounds that show promise in cancer chemotherapy and chemoprevention have been identified as farnesyltransferase inhibitors. These can be classified into mainly two different types of inhibitors, farnesyl diphosphate competitors and CAAX peptidomimetics. The former type acts by competitively inhibiting farnesyltransferase with respect to one of the substrates, farnesyl diphosphate, whereas the latter type acts by mimicking the other substrate, the C-terminal CAAX motif of Ras protein. One example of a farnesyl diphosphate competitor is manumycin, an antibiotic detected in the culture media of a Streptomyces strain. The CAAX peptidomimetics were developed based on the unique property of farnesyltransferase to recognize the CAAX motif at the C-terminus of the protein substrate. Our recent studies have focused on understanding the structural basis of this CAAX recognition. By using in vitro mutagenesis, residues of yeast farnesyltransferase important for the recognition of the CAAX motif have been identified. Two of these residues are closely located at the C-terminal region of the beta-subunit of farnesyltransferase. These and other results on the structural basis of the CAAX recognition may provide information valuable for structure-based design of farnesyltransferase inhibitors.
Yang
W
W
Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles 90095-1489, USA.
Del Villar
K
K
Urano
J
J
Mitsuzawa
H
H
Tamanoi
F
F
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase