Biomedical Engineering Reference
In-Depth Information
8.4.3 Bioactive secondary metabolites
Fungi are a particularly rich source of bioactive secondary metabolites with potent
physiological activities and possible pharmaceutical applications; these microbial
compounds continue to be a key source of molecules for drug discovery. More than half of
the isolated fungal compounds have antibacterial, antifungal or antitumor activity (Palaez,
2005), and 60% of anticancer agents and 70% of anti-infectives presently in clinical use are
natural products or natural product-based compounds (Yin et al ., 2007 ). Secondary
metabolites are synthesized by a few common biosynthetic pathways, often in conjunction
with a specific stage of morphological differentiation. The polyketide synthases (PKSs) and
non-ribosomal peptide synthetases (NRPSs) generate many of these biologically active
compounds. The conserved features within PKS and NRPS gene sequences are the
foundation for genomic-guided discovery of nature products. Bioinformatic analysis of
these biosynthetic genes in the burgeoning number of reported fungal genomes indicates
that these organisms encode the information for the production of a multitude of yet
undiscovered compounds.
A major obstacle for mining novel fungal metabolites is uncovering the conditions in
which they are synthesized. Because these compounds are not required for the organism's
growth or development, in the absence of a particular trigger these gene loci remain silent.
Genome mining has proven to be a fruitful approach for the discovery of novel microbial
metabolites. Bergmann and colleagues showed that an A. nidulans cryptic gene cluster could
be chemically switched on by the ectopic expression of the pathway specific regulator by an
inducible promoter (Bergmann et al ., 2007). The authors isolated and identified two novel
PKS-NRPS hybrid metabolites: the cytotoxic aspyridones A and B (Bergmann et al ., 2007 ).
Chiang and colleagues induced an otherwise silent pathway by a similar strategy to generate
the novel polyketide asperfuranone (Chiang et al ., 2009 ).
Some genes encoding specific fungal secondary metabolites are clustered near telomeres
or in heterochromatin regions, and their activation is controlled by regulation at the
chromatin level by processes that include DNA methylation and histone deacetylation.
This productive area of research was initiated with the discovery of laeA , a gene whose
deletion led to decreased expression of known secondary metabolites in a number of
Aspergilli (Bok and Keller, 2004). Deletion of hdaA , encoding an A. nidulans histone
deacetylase, relieved chromatin-level suppression of two secondary metabolites located in
the telomere region (Shwab et al ., 2005). Bok and colleagues showed that the loss-of-
function A. nidulans CclA, involved in histone H3 lysine 4 methylation, activated the
expression of cryptic secondary metabolite clusters and generated monodictyphenone and
anti-osteoporosis polyketides F9775A and F9775B (Bok et al ., 2009). Orthologues of laeA
have been identified in additional ascomycetes outside of the genus Aspergillus , including
Penicillium and Fusarium , and characterized (Wiemann et al ., 2010 ; Xing et al ., 2010 ;
Kosalkova et al ., 2009 ).
8.5 CONCLUSIONS
For centuries, fungi have been utilized by humans for their ability to convert complex and
simple substrates into more usable, palatable and/or valuable forms. Optimization of the
fungal strains and bioprocesses responsible for these amazing transformations takes time.
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