Sameh Soliman and and Yi Tang
Department of Medicinal Chemistry, School of Pharmacy, UOS, UAE; Department of Chemical and Biomolecular Engineering, Department of Chemistry and Biochemistry, Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, Los Angeles, California 90095, United States
UCS1025A is a novel polyketide-nonribosomal peptide (PK-NRP) hybrid fungal metabolite with a decalin-like structure. UCS1025A isolated from Acremonium fungus KY4917 (FERM) and exhibiting antibacterial and antiproliferative activities. Although it is known for a decade, its biosynthesis has not been elucidated. The gene cluster for USC1025A was predicted by bioinformatics analysis and its PKS-NRPS deletion mutation validates its essential role in UCS1025A biosynthesis. Heterogonous engineering of the gene cluster into Aspergillus nidulance (AN) using yeast recombination-based cloning strategy, was successfully performed. Only the gene cluster transformed without transcription factors (AN#2) was able to produce the compound. Activation of the UCS1025A gene cluster in the FERM fungus by over-expressing each transcription factor separately increased the compound production up to 4 times. Similarly activation of the gene cluster in A. nidulance transformed with the UCS1025A gene cluster containing transcription factors (AN#1) was able to detect affordable amount. Two transcription factors would work as activator and one as repressor. The UCS1025A gene cluster (1759) with another gene cluster (1590) comprised a branch of a phylogentic tree close to lovastatin gene cluster indicating similar compound could be produced by this cluster. This work will help in genetic manipulation and investigation of the UCS1025A biosynthetic pathway.