The C4 hydroxyl group of phorbol esters is not necessary for protein kinase C binding.
To investigate the role of the hydroxyl group at position 4 of the phorbol esters in protein kinase C (PKC) binding and function, 4beta-deoxy-phorbol-12,13-dibutyrate (4beta-deoxy-PDBu, 5a) and 4beta-deoxy-phorbol-13-acetate (6a) were synthesized from phorbol (1). The binding affinities of these 4beta-deoxy compounds (5a, 6a) to the 13 PKC isozyme C1 domains were quite similar to those of the corresponding 4beta-hydroxy compounds (4a, 4b), suggesting that the C4 hydroxyl group of phorbol esters is not necessary for PKC binding. Moreover, functional assays showed that 4beta-deoxy-PDBu (5a) exhibited biological activities (Epstein-Barr virus induction and superoxide generation) equally potent to those of PDBu (4a). These solution phase results differ from expectations based on the previously reported solid-phase structure of the complex of PKCdelta-C1B and phorbol-13-acetate (4b).
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan.
M
M
Tanaka
K
K
Irie
Y
Y
Nakagawa
Y
Y
Nakamura
H
H
Ohigashi
P A
PA
Wender
D000956:Antigens, Viral / Q000378:metabolism; D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010703:Phorbol Esters / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013481:Superoxides / Q000378:metabolism
D000956:Antigens, Viral; D002273:Carcinogens; C033305:Epstein-Barr virus early antigen; D010703:Phorbol Esters; D020033:Protein Isoforms; D013481:Superoxides; D011493:Protein Kinase C