title: Identification and engineering of the cytochalasin gene cluster from Aspergillus clavatus NRRL 1.
abstract: Cytochalasins are a group of fungal secondary metabolites with diverse structures and bioactivities, including cytochalasin E produced by Aspergillus clavatus, which is a potent anti-angiogenic agent. Here, we report the identification and characterization of the cytochalasin gene cluster from A. clavatus NRRL 1. As a producer of cytochalasin E and K, the genome of A. clavatus was analyzed and the ∼30 kb ccs gene cluster was identified based on the presence of a polyketide synthase-nonribosomal peptide synthetases (PKS-NRPS) and a putative Baeyer-Villiger monooxygenase (BVMO). Deletion of the central PKS-NRPS gene, ccsA, abolished the production of cytochalasin E and K, confirming the association between the natural products and the gene cluster. Based on bioinformatic analysis, a putative biosynthetic pathway is proposed. Furthermore, overexpression of the pathway specific regulator ccsR elevated the titer of cytochalasin E from 25mg/L to 175 mg/L. Our results not only shed light on the biosynthesis of cytochalasins, but also provided genetic tools for increasing and engineering the production.
authors: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA. qiaokangjian@ucla.edu
authors: Kangjian
authors: K
authors: Qiao
authors: Yit-Heng
authors: YH
authors: Chooi
authors: Yi
authors: Y
authors: Tang
mesh_terms: D001230:Aspergillus / Q000235:genetics / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics; D003572:Cytochalasins / Q000096:biosynthesis*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005818:Genetic Engineering; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D003572:Cytochalasins; D005656:Fungal Proteins; C007215:cytochalasin E; D006899:Mixed Function Oxygenases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase