Synthesis and characterization of inhibitors of myristoyl-CoA:protein N-myristoyltransferase.
Several substrate and product analogs were synthesized and tested as in vitro inhibitors of bovine brain N-myristoyl-CoA:protein N-myristoyltransferase (NMT; EC 2.3.1.97). At 40 microM, the acyl CoA analog, S-(2-ketopentadecyl)-CoA, completely inhibited NMT in the presence of 80 microM myristoyl CoA. Decreasing but marked inhibition was also observed with the acyl CoA analogs, S-(2-bromo-tetradecanoyl)-CoA and S-(3-(epoxymethylene)dodecanoyl)-CoA, and the multisubstrate derivative N-(2-S-CoA-tetradecanoyl)glycinamide in the presence of 40 microM myristoyl CoA. Inhibition was also observed with the non-coenzyme A myristoyl analog, 1-bromo-2-pentadecanone. All of the above compounds exhibited reversible competitive inhibition kinetics with respect to myristoyl CoA with Ki values of 0.11 to 24 microM. Two additional acyl CoA analogs, S-(cis-3-tetradecenoyl)-CoA and S-(3-tetradecynoyl)-CoA, functioned as alternative substrates for NMT.
Glover
C J
CJ
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Tellez
M R
MR
Guziec
F S
FS
Felsted
R L
RL
D000214:Acyl Coenzyme A / Q000737:chemistry* / Q000494:pharmacology; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D015195:Drug Design; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data
D000214:Acyl Coenzyme A; D007659:Ketones; C068047:1-bromo-2-pentadecanone; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase