Inverse stable isotopic labeling for natural product characterization and discovery

Covering: 2005 to 2026Stable isotopic labeling is a powerful tool in natural products research; however, the isotopically substituted precursors required for conventional labeling approaches are not always available. In such cases, inverse stable isotopic labeling (InverSIL) offers an effective alternative. In this approach, natural product producing organisms are grown on isotopically substituted media, which is then supplemented with precursors at their natural isotopic abundance. Incorporation of these unlabeled precursors can be readily detected due to their isotopic contrast, circumventing limitations associated with precursor availability. Here, we review applications of InverSIL in the characterization of natural product biosynthetic pathways and structures, as well as its use in genome mining to link biosynthetic genes to the natural products they produce. We also discuss contexts in which the InverSIL approach is particularly advantageous, as well as situations where its utility may be limited. Through this review, we aim to encourage broader adoption of InverSIL as a versatile strategy for advancing natural products research.