Short-Circuiting the SAM-Cycle in <i>Escherichia coli</i>

Enzyme-mediated transfer of methyl groups to specific nucleophilic functions on small metabolites, proteins, and nucleic acids is an essential activity in all known life forms. Most of these transferred methyl groups originate from the one-carbon metabolism through methyl-tetrahydrofolate-dependent methylation of homocysteine, followed by adenosylation of methionine to form the primary methyltransferase cofactor, <i>S</i>-adenosylmethionine (SAM). In this report, we describe a strain of <i>Escherichia coli</i> with a Short-Circuited SAM-Cycle (SCSC) that maintains its SAM pool exclusively by methylating <i>S</i>-adenosylhomocysteine (SAH) using a synthetic methyl donor. Construction of this strain was made possible by the identification of an aryl sulfonate methyl ester as a biocompatible methyl donor and methyltransferases that accept this compound as substrate for <i>in vivo</i> methylation of SAH. We exploited this organism for the optimization of SAH-methylating enzymes by <i>in vivo</i> selection and to produce isotope-labeled natural products. Looking ahead, we anticipate that strains with SCSCs will open new possibilities for methyltransferase biocatalysis, natural product discovery, and bacterial metabolomics.