Search

Regioselective S-acylation of coenzyme A (CoA) is achieved under aqueous conditions using various aliphatic and aromatic carboxylic acids activated as their methyl acyl phosphate monoesters. Unlike many hydrophobic activating groups, the anionic methyl acyl phosphate mixed anhydride is more compatible with aqueous solvents, making it useful for conducting acylation reactions in an aqueous medium.

Rational approaches for the design of enzyme inhibitors furnish powerful strategies for developing pharmaceutical agents and tools for probing biological mechanisms. A new strategy for the development of gem -disubstituted substrate-product analogues as inhibitors of racemases and epimerases is elaborated using α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis ( Mt MCR) as a model enzyme. Mt MCR catalyzes the epimerization at C 2 of acyl-CoA substrates, a key step in the metabolism of branched-chain fatty acids. Moreover, the human enzyme is a potential target for the development of therapeutic agents directed against prostate cancer. We show that rationally designed, N , N -dialkylcarbamoyl-CoA substrate-product analogues inactivate Mt MCR. Binding greatly exceeds that of the substrate, ( S )-ibuprofenoyl-CoA, up to ∼250-fold and is proportional to the alkyl chain length (4–12 carbons) with the N , N -didecyl and N , N -didodecyl species having competitive inhibition constants with values of 1.9 ± 0.2 μM and 0.42 ± 0.04 μM, respectively. The presence of two decyl chains enhanced binding over a single decyl chain by ∼204-fold. Overall, the results reveal that gem -disubstituted substrate-product analogues can yield extremely potent inhibitors of an epimerase with a capacious active site. [ABSTRACT FROM AUTHOR]