Genome mining and biosynthesis of the Acyl-CoA:cholesterol acyltransferase inhibitor beauveriolide I and III in Cordyceps militaris.

Ascomycete fungi Cordyceps are widely used in traditional Chinese medicine, and numerous investigations have been carried out to uncover their biological activities. However, primary researches on the physiological effects of Cordyceps were committed using crude extracts. At present, there are only a few compounds which were comprehensively characterized from Cordyceps, partial owing to the low production. In order to scientifically take advantage of Cordyceps, we used the strategy of genome mining to discover bioactive compounds from Cordyceps militaris. We found the putative biosynthetic gene cluster of the acyl-CoA:cholesterol acyltransferase inhibitor beauveriolides in the genome of C. militaris, and produced the compounds by heterologous expression in Aspergillus nidulans. Production of beauveriolide I and III also was detected in both ferment mycelia and fruiting bodies of C. militaris. The possible biosynthetic pathway was proposed. Our studies unveil the active compounds of C. militaris against atherosclerosis and Alzheimer's disease and provide the enzyme resources for the biosynthesis of new cyclodepsipeptide molecules.