Seven Cyclization Patterns of Type II PKS Yield Fluorescent Compounds, Including Fungal-Type Folded Globismycin A

Aromatic polyketides have emerged as an important source of fluorescent natural products, which hold significant value for research and diagnostic applications. In this study, we reported the discovery of three new (<b>5</b>, <b>6</b>, and <b>9</b>) and ten known (<b>1</b>-<b>4</b>, <b>7</b>, <b>8</b>, and <b>10</b>-<b>13</b>) fluorescent aromatic polyketides representing seven sets of carbon skeletons. Compounds <b>3</b>-<b>13</b> exhibited fluorescence ranging from cyan to orange-yellow and displayed varied behaviors in terms of excitation wavelength, emission wavelength, and Stokes shift, indicating their diverse spectral characteristics and environmental responsiveness. Notably, globismycin A (<b>5</b>) features an unprecedented 2,3-dihydrobenzofuro[4,5,6-de]chromene scaffold. Compound <b>5</b> not only exhibited high quantum yields in both water and organic solvents, with visible green fluorescence to the naked eye, but also showed potent selective cytotoxicity against three cancer cell lines. Biosynthetic investigations through a combination of gene inactivation, heterologous expression, and ¹³C-labeled acetate feeding studies revealed that these fluorescent compounds, despite differing in size and shape, are all derived from a type II polyketide synthase (PKS) gene cluster <i>sgl</i>, and their diverse skeletons are generated through seven distinct cyclization patterns. More importantly, compound <b>5</b> uniquely involves a characteristic fungal F-mode first-ring cyclization step, although <b>5</b> has been proven to be a bacterial aromatic polyketide. These findings not only provide excellent fluorescent candidates potentially useful for various biological applications but also expand our understanding on the biosynthetic mechanisms driving the production of diverse aromatic polyketides by type II gene clusters.