Aminoacylation of coenzyme A and pantetheine by aminoacyl-tRNA synthetases: possible link between noncoded and coded peptide synthesis.

Isoleucyl-tRNA synthetase (IleRS) catalyzes transfer of isoleucine from the enzyme-bound Ile-AMP and Ile-tRNA to the thiol group of coenzyme A, forming a thioester, Ile-S-CoA. Identity of Ile-S-CoA has been confirmed by several enzymatic and chemical tests. The synthesis of Ile-S-CoA, like the synthesis of other isoleucyl thioesters, is strongly shifted toward products. Other aminoacyl-tRNA synthetases, such as MetRS, AspRS, and SerRS also use CoA-SH as an acceptor for their cognate amino acids. Pantetheine also serves as an amino acid acceptor in reactions catalyzed by AspRS, IleRS, and MetRS, forming corresponding aminoacyl-S-pantetheine thioesters. It appears that CoA-SH reacts with activated amino acids by binding to each synthetase at a site, separate from the tRNA and ATP binding sites, that includes the thiol-binding subsite. These and other data support a hypothesis that the present-day aminoacyl-tRNA synthetases have originated from ancestral forms that were involved in noncoded thioester-dependent peptide synthesis, functionally similar to the present-day nonribosomal peptide synthesis by multi-enzyme thiotemplate systems.