Development of Aspergillus nidulans as a Flexible Heterologous Host for
Producing Polyketides and Nonribosomal Peptides
Clay Wang
University of Southern California
Aspergillus terreus, the producer of the cholesterol lowering statin lovastain, and
Penicilliumchrysogenum, the producer of the antibiotic penicillin, are well-known examples of
important natural product producing fungi used for industrial production. Rapid sequencing of
fungal and bacterial genomes has shown that these organisms have many cryptic natural
product biosynthesis pathways where their products are still unknown, the reason in most
cases being that they are not expressed in normal laboratory culture conditions. By
manipulating the expression of these natural product pathways we have been able to
overproduce the products and make them available for structural determination and biological
testing. We are developing A.nidulans as a heterologous host to express natural product
pathways from organisms where genetic tools are currently limited. We have chosen to work
with A. nidulans because there is a large number of genetic tools available for this wellestablished fungal model organism. Wild type A. nidulans produces copious amounts of natural
products; therefore, it has the precursor pool needed to produce large amounts of polyketides
and nonribosomal peptides. As another benefit, it also exhibits a fast rate of growth. Lastly, our
group and others have made significant inroads in characterizing its metabolome, which greatly
facilitates the identification of heterologously expressed compounds.
Core Capabilities at the Wang group at the University of Southern California:
Chemistry: Structural determination of natural products (polyketides, nonribosomal peptides,
and terpenes) by NMR and Mass Spectrometry. In house NMR, mass spec, natural product
computer database, and personnel available.
Biology: Experience in cloning large genes such as PKS and NRPS and multi-gene constructs.
Experience in genetic manipulation of fungi and bacteria.
Bioinformatics: Genome-wide analysis of bacterial and fungal genomes.
Representative Publications Relevant to Project:
1. Chiang, Y. et al., Recent advances in awakening silent biosynthetic gene clusters and linking
orphan clusters to natural products in microorganisms. Current Opinion in Chemical Biology
2011; 15: 137-143.
2. Chiang, Y. et al., Discovery of a polyketide, asperfuranone, and its biosynthetic gene cluster in
Aspergillus nidulans using a genome mining approach. J. Am. Chem. Soc. 2009; 131: 2965-2970.
3. Bok, J. W. et al., Chromatin-level regulation of cryptic biosynthetic gene clusters in Aspergillus
nidulans. Nature Chem. Biol. 2009; 5: 462-464.
4. Watanabe, K. et al., Total biosynthesis of antitumor nonribosomal peptides in Escherichia
coli. Nature Chem. Biol. 2006; 2: 398-400.