Identification of Ras farnesyltransferase inhibitors by microbial screening

Autor: Masami Okabe, Mitsunobu Hara, Shiro Akinaga, Douglas Wood, Misook Uh, Ruben Gomez, Fuyuhiko Tamanoi, Kazuhito Akasaka, Hirofumi Nakano
Rok vydání: 1993
Předmět:
Male
Polyunsaturated Alkamides
Fibrosarcoma
Recombinant Fusion Proteins
Farnesyltransferase
Genes
Fungal
Molecular Sequence Data
Transplantation
Heterologous
Farnesyl pyrophosphate
Mice
Nude
Polyenes
Saccharomyces cerevisiae
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Non-competitive inhibition
Transferases
Tumor Cells
Cultured
Animals
Humans
Structure–activity relationship
Amino Acid Sequence
Glutathione Transferase
Mice
Inbred BALB C
Alkyl and Aryl Transferases
Antibiotics
Antineoplastic
Multidisciplinary
Molecular Structure
biology
Brain
Biological activity
Streptomyces
Yeast
Anti-Bacterial Agents
Rats
Transplantation
Cell Transformation
Neoplastic
Genes
ras
Biochemistry
chemistry
Enzyme inhibitor
biology.protein
Cattle
Genes
Lethal
Neoplasm Transplantation
Research Article
Zdroj: Proceedings of the National Academy of Sciences. 90:2281-2285
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.90.6.2281
Popis: A microbial screen using a yeast strain with conditional deficiency in the GPA1 gene was carried out to search for inhibitors of protein farnesyltransferase (PFT). A strain of Streptomyces was found to produce active compounds named UCF1-A, UCF1-B, and UCF1-C. Structural determination of these compounds revealed that UCF1-C is identical to the known antibiotic, manumycin, whereas UCF1-A and UCF1-B are structurally related to manumycin. All three UCF1 compounds suppress the lethality of gpa1 disruption, with UCF1-C exhibiting the strongest activity. UCF1 inhibits yeast as well as rat brain PFT. Fifty percent inhibition of yeast PFT activity is observed with 5 microM UCF1-C. Kinetic analyses of the inhibition suggest that UCF1-C acts as a competitive inhibitor of PFT with respect to farnesyl pyrophosphate, exhibiting a Ki of 1.2 microM, whereas the same compound appears to act as a noncompetitive inhibitor of PFT with respect to the farnesyl acceptor, the Ras protein. UCF1-C shows significant activity to inhibit the growth of Ki-ras-transformed fibrosarcoma, raising the possibility of its use as an antitumor drug.
Databáze: OpenAIRE
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