How Sulfur Gets Into Polyketides: Unveiling the SH Domain's Magic

Ever wondered how some natural products get their sulfur touch? Polyketide synthases (PKSs) are like brilliant artists, painting diverse polyketide compounds. But they don't often dip into the sulfur paintbox. Enter thiocysteine lyase (SH) domains, found in the leinamycin (LNM) family. We've been studying these SH domains, like GnmT-SH, to figure out how they work. We started with a super detailed look at GnmT-SH's crystal structure, zooming in at 1. 8 Å resolution. We crafted special mimics to test our ideas, combining bioinformatics, molecular modeling, and lab tests. Guess what? We found out how these SH domains interact with acyl carrier proteins (ACPs) and their tethered substrates. Nature's pretty clever. It took a common protein structure and tweaked it to handle these big ACP-tethered substrates. This study shows how PLP-dependent chemistry can join the PKS party, paving the way for engineering PKSs to make sulfur-containing polyketides.