RESUMO
Lorneic acid and related natural products are characterized by a trialkyl-substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochromeâ P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl-substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450-catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochromeâ P450.
Assuntos
Policetídeos , Policetídeos/química , Benzeno , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Sistema Enzimático do Citocromo P-450 , Metabolismo SecundárioRESUMO
Genome mining of an indolocarbazole-type gene cluster from a marine-derived Nocardiopsis flavescens NA01583 strain led to the discovery of three new indolocarbazole alkaloids (1-3). Heterologous expression of the intact loo gene cluster in a surrogate host Streptomyces lividans K4-114 led to the successful production of 3. Notably, compound 1 showed potent cytotoxic activities toward eight cancer cell lines with IC50 values ranging from 41 to 283 nM.