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-mu-M, the acyl CoA analog, S-(2-ketopentadecyl)-CoA, completely inhibited NMT in the presence of 80-mu-M myristoyl CoA. Decreasing but marked inhibition was also observed with the acyl CoA analogs, S-(2-bromotetradecanoyl)-CoA and S-(3-epoxymethylene)dodecanoyl)-CoA, and the multisubstrate derivative N-(2-S-CoA-tetradecanoyl)glycinamide in the presence of 40-mu-M 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 K(i) values of 0.11 to 24-mu-M. Two additional acyl CoA analogs, S-(cis-3-tetradecenoyl)-CoA and S-(3-tetradecynoyl)-CoA, functioned as alternative substrates for NMT.