Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes

Campbell, Chantel D.; Vederas, John C.

doi:10.1002/bip.21428

Cited by 111 publications

(67 citation statements)

References 66 publications

(114 reference statements)

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“…Polyketides comprises diverse fungal secondary metabolites such as antibiotics, pigments, and mycotoxins that are formed from simple carbon precursor acids catalyzed by polyketide synthases (PKSs) [57]. Filamentous fungi are producers of polyketide metabolites, several of which of pharmacological or agricultural interest [58, 59]. Fungal PKSs are in general a linear succession of ketosynthetase (KS), acyltransferase (AT), dehydratase (DH), enoyl reductase (ER), ketoreductase (KR), acyl carrier protein (ACP), and thioesterase (TE) domains [60].…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis

et al. 2014

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BackgroundThe fungal genus Sporothrix includes at least four human pathogenic species. One of these species, S. brasiliensis, is the causal agent of a major ongoing zoonotic outbreak of sporotrichosis in Brazil. Elsewhere, sapronoses are caused by S. schenckii and S. globosa. The major aims on this comparative genomic study are: 1) to explore the presence of virulence factors in S. schenckii and S. brasiliensis; 2) to compare S. brasiliensis, which is cat-transmitted and infects both humans and cats with S. schenckii, mainly a human pathogen; 3) to compare these two species to other human pathogens (Onygenales) with similar thermo-dimorphic behavior and to other plant-associated Sordariomycetes.ResultsThe genomes of S. schenckii and S. brasiliensis were pyrosequenced to 17x and 20x coverage comprising a total of 32.3 Mb and 33.2 Mb, respectively. Pair-wise genome alignments revealed that the two species are highly syntenic showing 97.5% average sequence identity. Phylogenomic analysis reveals that both species diverged about 3.8-4.9 MYA suggesting a recent event of speciation. Transposable elements comprise respectively 0.34% and 0.62% of the S. schenckii and S. brasiliensis genomes and expansions of Gypsy-like elements was observed reflecting the accumulation of repetitive elements in the S. brasiliensis genome. Mitochondrial genomic comparisons showed the presence of group-I intron encoding homing endonucleases (HE’s) exclusively in S. brasiliensis. Analysis of protein family expansions and contractions in the Sporothrix lineage revealed expansion of LysM domain-containing proteins, small GTPases, PKS type1 and leucin-rich proteins. In contrast, a lack of polysaccharide lyase genes that are associated with decay of plants was observed when compared to other Sordariomycetes and dimorphic fungal pathogens, suggesting evolutionary adaptations from a plant pathogenic or saprobic to an animal pathogenic life style.ConclusionsComparative genomic data suggest a unique ecological shift in the Sporothrix lineage from plant-association to mammalian parasitism, which contributes to the understanding of how environmental interactions may shape fungal virulence. . Moreover, the striking differences found in comparison with other dimorphic fungi revealed that dimorphism in these close relatives of plant-associated Sordariomycetes is a case of convergent evolution, stressing the importance of this morphogenetic change in fungal pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-943) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis

et al. 2014

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“…The structural similarity of 1 , 2 and lovastatin 3 suggested that the decalin core of 1 may be formed by an intramolecular DA reaction, as proposed for the biocatalytic formation of the decalin cores of 2 and 3 (Figure 1B). [12] To gain further insight into the mechanism of biosynthesis of 1 and to determine if a DA reaction is indeed involved in the biosynthesis of 1 , we identified the C. globosum gene cluster responsible for the biosynthesis of 1 for a detailed investigation.…”

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confidence: 99%

Involvement of Lipocalin‐like CghA in Decalin‐Forming Stereoselective Intramolecular [4+2] Cycloaddition

et al. 2015

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Understanding enzymatic Diels—Alder (DA) reactions that can form complex natural product scaffold is of considerable interest. Sch 210972 1, a potential anti-HIV fungal natural product, contains a decalin core that is proposed to form via a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo 1 and a diastereomeric exo adducts of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin-like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1.

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“…In a fungal context, it is a compound that blocks the first step of the terpene biosynthesis for the production of ergosterol (the main component of cell membranes in fungi). It was first discovered in Aspergillus terreus and is a precursor of other successful anti-cholesterol drugs [45]. However, the antifungal properties of some statins have been known for years and recent studies have shown that statins bring to bear relevant antifungal effects against dermatophyte fungi and, in combination with other clinically used antifungal agents, can significantly improve the treatment using combined therapy [46].…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Protein Domain and Domain Architecture Content in Fungi and Its Application in the Search of New Antifungal Targets

et al. 2014

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Over the past several years fungal infections have shown an increasing incidence in the susceptible population, and caused high mortality rates. In parallel, multi-resistant fungi are emerging in human infections. Therefore, the identification of new potential antifungal targets is a priority. The first task of this study was to analyse the protein domain and domain architecture content of the 137 fungal proteomes (corresponding to 111 species) available in UniProtKB (UniProt KnowledgeBase) by January 2013. The resulting list of core and exclusive domain and domain architectures is provided in this paper. It delineates the different levels of fungal taxonomic classification: phylum, subphylum, order, genus and species. The analysis highlighted Aspergillus as the most diverse genus in terms of exclusive domain content. In addition, we also investigated which domains could be considered promiscuous in the different organisms. As an application of this analysis, we explored three different ways to detect potential targets for antifungal drugs. First, we compared the domain and domain architecture content of the human and fungal proteomes, and identified those domains and domain architectures only present in fungi. Secondly, we looked for information regarding fungal pathways in public repositories, where proteins containing promiscuous domains could be involved. Three pathways were identified as a result: lovastatin biosynthesis, xylan degradation and biosynthesis of siroheme. Finally, we classified a subset of the studied fungi in five groups depending on their occurrence in clinical samples. We then looked for exclusive domains in the groups that were more relevant clinically and determined which of them had the potential to bind small molecules. Overall, this study provides a comprehensive analysis of the available fungal proteomes and shows three approaches that can be used as a first step in the detection of new antifungal targets.

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Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes

Cited by 111 publications

References 66 publications

Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis

Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis

Involvement of Lipocalin‐like CghA in Decalin‐Forming Stereoselective Intramolecular [4+2] Cycloaddition

Analysis of the Protein Domain and Domain Architecture Content in Fungi and Its Application in the Search of New Antifungal Targets

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