Overexpression of the Global Regulator LaeA in Chaetomium globosum Leads to the Biosynthesis of Chaetoglobosin Z

Abstract

Overexpression of laeA in Chaetomium globosum CBS148.51 up-regulated expression of the chaetoglobosin gene cluster and resulted in the isolation of a new cytochalasan, chaetoglobosin Z (1), together with six known analogues, chaetoglobosins A (2), B (3), D (4), E (5), O (6), and V (7). RT-PCR analysis confirmed that the key genes in the chaetoglobosin gene cluster were significantly up-regulated. The structure of the new compound chaetoglobosin Z (1) was elucidated using NMR data. The relative and absolute configurations were determined by NOESY and electronic circular dichroism combined with quantum-chemical calculations adopting time-dependent density functional theory methods, respectively. These compounds displayed strong biological effects against the HepG 2 cell line compared with the positive control. The results further supported that LaeA is a global regulator that could up-regulate and/or activate cryptic gene clusters to produce new secondary metabolites.

Gα-cAMP/PKA pathway positively regulates pigmentation, chaetoglobosin A biosynthesis and sexual development in Chaetomium globosum

“…The roles of VeA and LaeA on secondary metabolism in C . globosum was confirmed by studies of Watanabe and Zou teams [ 24 , 40 ]. Deletion of either CglaeA or CgVeA led to a significant absence of many secondary metabolites including ChA [ 24 ], whereas overexpression of CglaeA upregulated expression of the chaetoglobosin gene cluster and resulted in the isolation of a new cytochalasin, chaetoglobosin Z [ 40 ], demonstrating positive regulatory activity of CglaeA and CgVeA on ChA biosynthesis in C .…”

Diagnostically analyzing 1H NMR spectra of sub-types in chaetoglobosins for dereplication

“…The compounds in this report have been isolated and characterized previously in the authors' laboratories. [26][27][28] 4.2 NMR Spectroscopy…”

Strategies to diversify natural products for drug discovery

“…Overexpression of laeA in Chaetomium globsum upregulated expression of the chaetoglobosin biosynthetic pathway and enabled the isolation and characterization of a new cytotoxic cytochalasan, chaetoglobosin Z ( 53 ) (Fig. ), of hybrid PKS/NRPS origin . Furthermore, overexpression of laeA is required to increase production of the β ‐lactam antibiotic penicillin ( 54 ) in Penicillium chrysogenum and the notorious mycotoxin aflatoxin B1 ( 55 ) in Aspergillus flavus .…”

“…18), of hybrid PKS/NRPS origin. 191 Furthermore, overexpression of laeA is required to increase production of the -lactam antibiotic penicillin (54) in Penicillium chrysogenum 192 and the notorious mycotoxin aflatoxin B1 (55) in Aspergillus flavus. 193 In contrast, knockout of laeA drastically reduced the expression levels of specialized metabolite BGC.…”