Nucleic Acids Res. 2026 May 11:gkag471. doi: 10.1093/nar/gkag471. Online ahead of print.

ABSTRACT

The design of pathways to synthesize valuable molecules remains a central challenge in chemistry and biotechnology. Several computational retrosynthesis tools have been developed to address this problem, but their scope is often confined only to reactions in either synthetic organic chemistry or monofunctional enzymatic chemistry. We present TridentSynth, a web-based retrosynthesis tool (https://tridentsynth.lbl.gov) to scale synthesis planning up to three different routes by also incorporating multifunctional Type I polyketide synthase (PKS) enzymes into our reaction toolkit along with organic chemistry and monofunctional enzymes. Unlike monofunctional enzymes that catalyze single transformations, PKSs function as molecular assembly lines that catalyze multiple carbon-carbon bond formation reactions between acyl-coenzyme A substrates to construct elongated carbon scaffolds. PKSs follow a modular, programmable logic that allows them to be reconfigured to make new molecules in a predictable way. These scaffolds can then be chemoenzymatically modified to eventually access a wider array of molecular targets than would be possible with just synthetic chemistry or monofunctional enzymes alone, in a manner that mimics the evolved biosynthesis routes of many useful natural products. TridentSynth assists synthetic biologists by suggesting routes to synthesize a desired molecule through an intuitive web interface that requires no local installation or programming expertise.

PMID:42109178 | DOI:10.1093/nar/gkag471