Total Synthesis of the Fungal Metabolite Trienylfuranol A through Nucleophilic Diastereodivergent Additions to Oxocarbenium Ions (original) (raw)
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5-hydroxymethylfurfural conversion by fungal aryl-alcohol oxidase and unspecific peroxygenase
FEBS Journal, 2015
Oxidative conversion of 5-hydroxymethylfurfural (HMF) is of biotechnological interest for the production of renewable (lignocellulose-based) platform chemicals, such as 2,5-furandicarboxylic acid (FDCA). To the best of our knowledge, the ability of fungal aryl-alcohol oxidase (AAO) to oxidize HMF is reported here for the first time, resulting in almost complete conversion into 2,5-formylfurancarboxylic acid (FFCA) in a few hours. The reaction starts with alcohol oxidation, yielding 2,5-diformylfuran (DFF), which is rapidly converted into FFCA by carbonyl oxidation, most probably without leaving the enzyme active site. This agrees with the similar catalytic efficiencies of the enzyme with respect to oxidization of HMF and DFF, and its very low activity on 2,5-hydroxymethylfurancarboxylic acid (which was not detected by GC-MS). However, AAO was found to be unable to directly oxidize the carbonyl group in FFCA, and only modest amounts of FDCA are formed from HMF (most probably by chemical oxidation of FFCA by the H2 O2 previously generated by AAO). As aldehyde oxidation by AAO proceeds via the corresponding geminal diols (aldehyde hydrates), the various carbonyl oxidation rates may be related to the low degree of hydration of FFCA compared with DFF. The conversion of HMF was completed by introducing a fungal unspecific heme peroxygenase that uses the H2 O2 generated by AAO to transform FFCA into FDCA, albeit more slowly than the previous AAO reactions. By adding this peroxygenase when FFCA production by AAO has been completed, transformation of HMF into FDCA may be achieved in a reaction cascade in which O2 is the only co-substrate required, and water is the only by-product formed.
Fungal anticancer metabolites: synthesis towards drug discovery
Current Medicinal Chemistry, 2017
Background: Fungi are a well-known and valuable source of compounds of therapeutic relevance, in particular of novel anticancer compounds. Although seldom obtainable through isolation from the natural source, the total organic synthesis still remains one of the most efficient alternatives to resupply them. Furthermore, natural product total synthesis is a valuable tool not only for discovery of new complex biologically active compounds but also for the development of innovative methodologies in enantioselective organic synthesis. Methods: We undertook an in-depth literature searching by using chemical bibliographic databases (SciFinder, Reaxys) in order to have a comprehensive insight into the wide research field. The literature has been then screened, refining the obtained results by subject terms focused on both biological activity and innovative synthetic procedures. Results: The literature on fungal metabolites has been recently reviewed and these publications have been used as ...
Manipulation of fungal development as source of novel secondary metabolites for biotechnology
Applied microbiology and biotechnology, 2014
Fungal genomics revealed a large potential of yet-unexplored secondary metabolites, which are not produced during vegetative growth. The discovery of novel bioactive compounds is increasingly gaining importance. The high number of resistances against established antibiotics requires novel drugs to counteract increasing human and animal mortality rates. In addition, growth of plant pathogens has to be controlled to minimize harvest losses. An additional critical issue is the post-harvest production of deleterious mycotoxins. Fungal development and secondary metabolite production are linked processes. Therefore, molecular regulators of development might be suitable to discover new bioactive fungal molecules or to serve as targets to control fungal growth, development, or secondary metabolite production. The fungal impact is relevant as well for our healthcare systems as for agriculture. We propose here to use the knowledge about mutant strains discovered in fungal model systems for a ...
Dual Induction of New Microbial Secondary Metabolites by Fungal Bacterial Co-cultivation
Frontiers in microbiology, 2017
The frequent re-isolation of known compounds is one of the major challenges in drug discovery. Many biosynthetic genes are not expressed under standard culture conditions, thus limiting the chemical diversity of microbial compounds that can be obtained through fermentation. On the other hand, the competition during co-cultivation of two or more different microorganisms in most cases leads to an enhanced production of constitutively present compounds or an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain under different fermentation conditions. Herein, we report the dual induction of newly detected bacterial and fungal metabolites by the co-cultivation of the marine-derived fungal isolate Aspergillus fumigatus MR2012 and two hyper-arid desert bacterial isolates Streptomyces leeuwenhoekii strain C34 and strain C58. Co-cultivation of the fungal isolate MR2012 with the bacterial strain C34 led to the production of luteoride D, a new lute...
Biotechnology for biofuels, 2018
2,5-Furandicarboxylic acid is a renewable building block for the production of polyfurandicarboxylates, which are biodegradable polyesters expected to substitute their classical counterparts derived from fossil resources. It may be produced from bio-based 5-hydroxymethylfurfural or 5-methoxymethylfurfural, both obtained by the acidic dehydration of biomass-derived fructose. 5-Methoxymethylfurfural, which is produced in the presence of methanol, generates less by-products and exhibits better storage stability than 5-hydroxymethylfurfural being, therefore, the industrial substrate of choice. In this work, an enzymatic cascade involving three fungal oxidoreductases has been developed for the production of 2,5-furandicarboxylic acid from 5-methoxymethylfurfural. Aryl-alcohol oxidase and unspecific peroxygenase act on 5-methoxymethylfurfural and its partially oxidized derivatives yielding 2,5-furandicarboxylic acid, as well as methanol as a by-product. Methanol oxidase takes advantage of...
Journal of Natural Products, 2013
The co-cultivation of fungi has recently been described as a promising strategy to induce the production of novel metabolites through possible gene activation. A large screening of fungal co-cultures in solid media has identified an unusual long-distance growth inhibition between Trichophyton rubrum and Bionectria ochroleuca. To study metabolite induction in this particular fungal interaction, differential LC-MS-based metabolomics was performed on pure strain cultures and on their co-cultures. The comparison of the resulting fingerprints highlighted five de novo induced compounds, which were purified using software-oriented semipreparative HPLC-MS. One metabolite was successfully identified as 4″-hydroxysulfoxy-2,2″-dimethylthielavin P (a substituted trimer of 3,5-dimethylorsellinic acid). The nonsulfated form, as well as three other related compounds, were found in the pure strain culture of B. ochroleuca.
Microbial Cell Factories
Background: Steroid compounds with a 6,19-oxirane bridge possess interesting biological activities including anticonvulsant and analgesic properties, bacteriostatic activity against Gram-positive bacteria and selective anti-glucocorticoid action, while lacking mineralocorticoid and progestagen activity. Results: The study aimed to obtain new derivatives of 3β-acetyloxy-5α-chloro-6,19-oxidoandrostan-17-one by microbial transformation. Twelve filamentous fungal strains were used as catalysts, including entomopathogenic strains with specific activity in the transformation of steroid compounds. All selected strains were characterised by high biotransformation capacity for steroid compounds. However, high substrate conversions were obtained in the cultures of 8 strains: Beauveria bassiana KCh BBT, Beauveria caledonica KCh J3.4, Penicillium commune KCh W7, Penicillium chrysogenum KCh S4, Mucor hiemalis KCh W2, Fusarium acuminatum KCh S1, Trichoderma atroviride KCh TRW and Isaria farinosa KCh KW1.1. Based on gas chromatography (GC) and nuclear magnetic resonance (NMR) analyses, it was found that almost all strains hydrolysed the ester bond of the acetyl group. The strain M. hiemalis KCh W2 reduced the carbonyl group additionally. From the P. commune KCh W7 and P. chrysogenum KCh S4 strain cultures a product of D-ring Baeyer-Villiger oxidation was isolated, whereas from the culture of B. bassiana KCh BBT a product of hydroxylation at the 11α position and oxidation of the D ring was obtained. Three 11α-hydroxy derivatives were obtained in the culture of I. farinosa KCh KW1.1: 3β,11α-dihydroxy-5α-chloro-6,19-oxidoandrostan-17-one, 3β,11α,19-trihydroxy-5α-chloro-6,19-oxidoandrostan-17-one and 3β,11α-dihydroxy-5α-chloro-6,19-oxidoandrostan-17,19-dione. They are a result of consecutive reactions of hydrolysis of the acetyl group at C-3, 11α-hydroxylation, then hydroxylation at C-19 and its further oxidation to lactone. Conclusions: As a result of the biotransformations, seven steroid derivatives, not previously described in the literature, were obtained: 3β-hydroxy-5α-chloro-6,19-oxidoandrostan-17-one, 3β,17α-dihydroxy-5α-chloro-6,19oxidoandrostane, 3β-hydroxy-5α-chloro-17α-oxa-D-homo-6,19-oxidoandrostan-17-one, 3β,11α-dihydroxy-5α-chloro-17α-oxa-D-homo-6,19-oxidoandrostan-17-one and the three above-mentioned 11α-hydroxy derivatives. This study will allow a better understanding and characterisation of the catalytic abilities of individual microorganisms, which is crucial for more accurate planning of experiments and achieving more predictable results.
Synthesis of Highly Functionalised Furo[3,4-b]pyrans: Towards the Fungal Metabolite (−)-TAN-2483B
Carbohydrate-derived cyclopropanes combine both the stereochemical wealth of carbohydrates and the reactivity of cyclopropanes. A diverse variety of reaction modes for these cyclopropyl carbohydrates can be harnessed for the synthesis of natural products and other targets. The natural products (−)-TAN-2483A and (−)-TAN-2483B are fungal secondary metabolites displaying a variety of bioactivities such as inhibition of c-src kinase action and parathyroid hormone-induced bone resorption. This thesis described several synthetic approaches to the natural product (−)-TAN-2483B and analogues of (−)-TAN-2483B employing cyclopropane ring expansion. The synthetic route to (−)-TAN-2483B began with the readily available substrate D-mannose. The pyran ring unsaturation of the natural product was established by a cyclopropanation-ring expansion sequence. A synthetic strategy via dichlorocyclopropane-based intermediates is described in chapter 2. This being unsuccessful, an alternative approach v...
Microorganisms
Substantial progress has been achieved and knowledge gaps addressed in synthetic biology-mediated engineering of biological organisms to produce high-value metabolites. Bio-based products from fungi are extensively explored in the present era, attributed to their emerging importance in the industrial sector, healthcare, and food applications. The edible group of fungi and multiple fungal strains defines attractive biological resources for high-value metabolites comprising food additives, pigments, dyes, industrial chemicals, and antibiotics, including other compounds. In this direction, synthetic biology-mediated genetic chassis of fungal strains to enhance/add value to novel chemical entities of biological origin is opening new avenues in fungal biotechnology. While substantial success has been achieved in the genetic manipulation of economically viable fungi (including Saccharomyces cerevisiae) in the production of metabolites of socio-economic relevance, knowledge gaps/obstacles ...