Hidden biosynthetic treasures brought to light

Hertweck, Christian

doi:10.1038/nchembio0709-450

Cited by 158 publications

(119 citation statements)

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“…Generation of novelty through exchange of domains between biosynthetic gene clusters polished under evolutionary selection pressure, invariably results in successful product assembly -as millions of failed experiments were rapidly discarded by natural selection. It is hypothesized that diversification of polyketides can occur in four steps throughout biosynthesis resulting from: (i) choice of polyketide building blocks and chain length; (ii) the extent of reduction and stereochemistry of -keto intermediates primary cyclization, alkylation and branching; (iii) rearrangements and secondary cyclization, and (iv) post-polyketide tailoring: glycosylation and oxygenation 50,51 . Therefore, the presence of a large number of polyketides and orphan polyketides indicates that M. phaseolina may possess sophisticated genetic mechanisms that facilitate its adaptation to heterogenous environments such as soil and living plant host.…”

Section: Resultsmentioning

confidence: 99%

Computational Analysis Reveals Industrial Natural Products and Toxins in Charcoal Rot Pathogen, <i>Macrophomina phaseolina</i>

Thakur¹,

Jana²

2017

Current Science

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The fungal polyketide synthases (PKS) are responsible for the biosynthesis of several polyketide natural products, mycotoxins, pigments, etc. In the present times, we use computational tools to gain insight into polyketide natural products that may contribute to the metabolic versatility of this important phytopathogenic filamentous fungi. In total, we have identified 17 type-I PKS related gene clusters from the Macrophomina phaseolina genome. Among these 27 ketosynthase (KS) domains have been retrieved and used for the study. The study reveals that genome of M. phaseolina comprises non-reducing (NR), partially reducing (PR) and reducing (R) type of polyketides, and are clustered into three clades and several subclades. The phylogenetic analysis of KS domain sequences of M. phaseolina indicates that some PKS sequences are most closely related to polyketide natural product homologs such as lovastatin diketide, mycotoxins (fumonisin, citrinin and patulin) and pigment melanin. We also found eight orphan KS domains from three reducing PKS, i.e. MPH10374, MPH10375 and MPH10376. The study represents a potential novel source of industrially important polyketide natural products.

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Section: Resultsmentioning

confidence: 99%

Computational Analysis Reveals Industrial Natural Products and Toxins in Charcoal Rot Pathogen, <i>Macrophomina phaseolina</i>

Thakur¹,

Jana²

2017

Current Science

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“…In contrast to the direct bioprospecting with known medicinal plants (the common problem being that of dereplication), exciting possibilities exist for exploiting endophytic fungi for the production of a plethora of known and novel biologically active secondary metabolites. The potential of microorganisms is further limited by the presence of orphan biosynthetic pathways that remain unexpressed under general laboratory conditions [31]. However, the vast choice of techniques pertaining to the growth and manipulation of microorganisms such as media engineering, coculture, chemical induction, epigenetic modulation and metabolite remodeling, coupled with the fermentation technology for scale-up, make them suitable for production of useful natural products, both known and novel [16].…”

Section: Endophytic Fungi and Search For Active Metabolitesmentioning

confidence: 99%

Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents

Omeje¹,

Ahomafor²,

Onyekaba³

et al. 2017

Natural Products and Cancer Drug Discovery

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In comparison with other natural sources like plants, highly diverse microorganisms are narrowly explored, especially with respect to their limitless potentials as repositories of exceptionally bioactive natural products. Of these organisms, fungi inhabiting tissues of plant in a noninvasive relationship (endophytic fungi) have proven undeniably useful and unmatchable as sources of potent bioactive molecules against several diseases such as cancer and related ailments. In general terms, endophytic fungi are highly prevalent organisms found in the tissue (intracellular or intercellular) of plants and at least for reasonable portion of their lives. It has been proven that virtually every plant, irrespective of habitat and climate, plays host to wide varieties of endophytes. Endophytic fungi produce metabolites produced by diferent biosynthetic pathways to that of the host plant, and this robustness equips them to synthesize unlimited structural entities and scafolds of diverse classes. Interestingly too, the cohabitation/culture of these fungi with certain bacteria ofers even stronger hopes for anticancer drug discovery. The endless need for potent drugs has necessitated the search of bioactive molecules from several sources, and endophytic fungi appear to be a recipe. This chapter is an atempt to present the current trend of research with these very promising organisms.

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“…1,2 Through recent whole-genome sequencing projects, however, we become increasingly aware that the biosynthetic potential of microorganisms is much higher than expected. 3 In many cases, the number of putative biosynthetic genes of fungi and bacteria is not reflected by the metabolic profile observed under laboratory culture conditions. Several gene loci encoding diverse metabolic pathways seem to lack expression in the absence of particular physical or chemical stimuli.…”

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confidence: 99%

Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans

et al. 2010

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Filamentous fungi produce a multitude of bioactive natural products, which cover a broad range of useful pharmaceutical activities. Many of these compounds were discovered by traditional natural product screening approaches and have found various applications in modern medicine. 1,2 Through recent whole-genome sequencing projects, however, we become increasingly aware that the biosynthetic potential of microorganisms is much higher than expected. 3 In many cases, the number of putative biosynthetic genes of fungi and bacteria is not reflected by the metabolic profile observed under laboratory culture conditions. Several gene loci encoding diverse metabolic pathways seem to lack expression in the absence of particular physical or chemical stimuli. 4 Mining the genome of Aspergillus nidulans for putative biosynthesis gene clusters revealed biosynthetic abilities for the production of up to 28 polyketides and 24 nonribosomally synthesized peptides. 5,6 However, this abundance of gene clusters clearly outnumbers the known secondary metabolites of this fungus. To gain access to this untapped reservoir of potentially bioactive natural products, various strategies to induce the expression of silent genes have been developed. 4,7 Important recent examples involve the ectopic expression of a regulatory gene, 8 the induction of a transcription activator by promotor exchange, 9 as well as modulation of the epigenetic regulation of biosynthetic genes at the chromatin level. [10][11][12][13] Furthermore, it was shown that the intimate contact between A. nidulans and a soil-dwelling actinomycete may lead to the specific induction of a cryptic polyketide gene cluster. 14 These strategies resulted in the discovery of a set of novel secondary metabolites, which could not be located by classical screening methods. Another option often preceding genomic approaches is the systematic investigation of the microbial secondary metabolome under various growth conditions. Since the early days of fermentations, it is known that the choice of the cultivation parameters is critical to the number and type of secondary metabolites produced by microorganisms. 4 Thus, the formation of cryptic natural products can up to a certain extent be triggered by a systematic variation of standard fermentation parameters to increase the number of secondary compounds produced in the bacterial or fungal culture. 15,16 On the basis of the assumption that changing environmental conditions can shift the metabolic profile of an organism, we systematically varied the cultivation parameters to reinvestigate the metabolome of A. nidulans. In this study, we report the discovery of two new isoindole alkaloids, aspernidine A (1) and B (2), as an addition to the metabolic data of this important model fungus (Figure 1a). An A. nidulans extract library was prepared by adjusting 45 different culture conditions (variation of culture media, cultivation period, temperature and oxygen supply) and the metabolic profiles were screened by HPLC-DAD-MS. Investigation of the cultur...

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Hidden biosynthetic treasures brought to light

Cited by 158 publications

References 23 publications

Computational Analysis Reveals Industrial Natural Products and Toxins in Charcoal Rot Pathogen, <i>Macrophomina phaseolina</i>

Computational Analysis Reveals Industrial Natural Products and Toxins in Charcoal Rot Pathogen, <i>Macrophomina phaseolina</i>

Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents

Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans

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