25] Synthesis of nonhydrolyzable acyl-coenzyme A analogs

Abstract

This chapter describes the chemical synthesis of different precursors of the nonhydrolyzable acyl–CH 2 CoA derivatives. The final synthesis of various nonhydrolyzable acyl–CH 2 CoA derivatives is also described. The activity of pantetheine phosphate adenylyltransferase is assayed in the reverse direction by monitoring the production of ATP from dephospho–CoA and PP i . Dephospho–CoA kinase is assayed by monitoring the production of ADP from dephospho-CoA and ATP by using the standard pyruvate kinase/lactate dehydrogenase coupling enzyme system. The two key intermediates for the chemical synthesis of acyldethia-coenzyme A analogs are acyldethia(carba)pantetheine 4-phosphate and adenosine 2',3'-cyclophosphate 5'-phosphomorpholidate. The final steps in the synthesis of acyl–CH 2 CoA depend on whether its precursors are obtained by the chemical or the chemoenzymatic strategy. Nonhydrolyzable acyl–CoA analogs are useful as alternative substrates, inhibitors, and regulators of a large number of enzymatic reactions. Their enhanced stability may be advantageous not only in mechanistic investigations but also in drug development. The chapter describes some conventional chemical syntheses of nonhydrolyzable acyl–CoA analogs and also a more recent chemoenzymatic strategy for their preparation.