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Special Issue "Biosynthesis of Natural Products"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (20 July 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Tobias A. M. Gulder

Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstraße 4, 85748 Garching, Germany
Website | E-Mail
Interests: natural product biosynthesis; biocatalysis; chemo-enzymatic synthesis; metabolic engineering

Special Issue Information

Dear Colleagues,

In the course of evolution, Nature has developed a very large variety of biocatalysts to produce an inexhaustible diversity of biologically active natural products. Understanding the principles of their biosynthesis is not only of high academic value, but also facilitates the directed manipulation of biosynthetic pathways, e.g., to enhance compound production titers or to optimize structures for biomedical applications. In addition, many natural product biosynthetic enzymes catalyze reactions not yet addressable by synthetic chemists and, thus, may be valuable biocatalytic tools. The field of natural product biosynthesis is therefore an exciting current and future scientific playground, with tremendous potential across chemical, biomolecular and biomedical disciplines.

In this Special Issue, we welcome research articles and reviews across the broad field of natural product biosynthesis, ranging from interrogating whole natural product pathways or individual enzymes to the manipulation of biosynthetic machineries.

As Guest Editor, I cordially invite researchers to submit their recent advances in the field to this Special Issue of Molecules.

Prof. Dr. Tobias A. M. Gulder
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Natural Products
  • Biosynthesis
  • Regulation
  • Bioengineering
  • Biocatalysis
  • Mutasynthesis
  • Polyketides
  • Non-ribosomal peptides
  • Ribosomal peptides
  • RiPPs
  • Terpenes
  • Alkaloids

Published Papers (8 papers)

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Research

Open AccessCommunication Characterisation of the Broadly-Specific O-Methyl-transferase JerF from the Late Stages of Jerangolid Biosynthesis
Molecules 2016, 21(11), 1443; doi:10.3390/molecules21111443
Received: 4 October 2016 / Revised: 20 October 2016 / Accepted: 21 October 2016 / Published: 29 October 2016
Cited by 1 | PDF Full-text (6243 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We describe the characterisation of the O-methyltransferase JerF from the late stages of jerangolid biosynthesis. JerF is the first known example of an enzyme that catalyses the formation of a non-aromatic, cyclic methylenolether. The enzyme was overexpressed in E. coli and the
[...] Read more.
We describe the characterisation of the O-methyltransferase JerF from the late stages of jerangolid biosynthesis. JerF is the first known example of an enzyme that catalyses the formation of a non-aromatic, cyclic methylenolether. The enzyme was overexpressed in E. coli and the cell-free extracts were used in bioconversion experiments. Chemical synthesis gave access to a series of substrate surrogates that covered a broad structural space. Enzymatic assays revealed a broad substrate tolerance and high regioselectivity of JerF, which makes it an attractive candidate for an application in chemoenzymatic synthesis with particular usefulness for late stage application on 4-methoxy-5,6-dihydro-2H-pyran-2-one-containing natural products. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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Open AccessArticle Alkyl-Substituted δ-Lactones Derived from Dihydrojasmone and Their Stereoselective Fungi-Mediated Conversion: Production of New Antifeedant Agents
Molecules 2016, 21(9), 1226; doi:10.3390/molecules21091226
Received: 18 July 2016 / Revised: 4 September 2016 / Accepted: 8 September 2016 / Published: 13 September 2016
PDF Full-text (1598 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A chemoenzymatic method was applied to obtain optically pure alkyl-substituted δ-lactones. First, chemical Baeyer–Villiger oxidation of dihydrojasmone (1) was carried out, affording two new alkyl-substituted δ-lactones: 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one (2) and 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (3). In the next step,
[...] Read more.
A chemoenzymatic method was applied to obtain optically pure alkyl-substituted δ-lactones. First, chemical Baeyer–Villiger oxidation of dihydrojasmone (1) was carried out, affording two new alkyl-substituted δ-lactones: 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one (2) and 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (3). In the next step, fungal strains were investigated as biocatalysts to enantioselective conversion of δ-lactones (2) and (3). The fungal cultures: Fusarium culmorum AM10, Fusarium equiseti AM15 and Beauveria bassiana AM278 catalyzed the stereoselective hydration of the double bond of lactone (2) (ee = 20%–99%) while Didymosphaeria igniaria KCh6670 proved to be the best biocatalyst for the reduction of carbonyl group in the epoxylactone (3) (ee = 99%). In both cases, chiral oxyderivatives were obtained in low to high yields (7%–91%). The synthetic lactones (2), (3) and its derivatives (4), (5) were tested for their antifeedant activity towards larvae and adults of lesser mealworm (Alphitobius diaperinus Panzer) and peach potato aphid (Myzus persicae [Sulzer]) and some of them were active towards studied insects. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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Open AccessArticle Adaptive Responses to Oxidative Stress in the Filamentous Fungal Shiraia bambusicola
Molecules 2016, 21(9), 1118; doi:10.3390/molecules21091118
Received: 30 June 2016 / Revised: 1 August 2016 / Accepted: 19 August 2016 / Published: 24 August 2016
Cited by 3 | PDF Full-text (2615 KB) | HTML Full-text | XML Full-text
Abstract
Shiraia bambusicola can retain excellent physiological activity when challenged with maximal photo-activated hypocrellin, which causes cellular oxidative stress. The protective mechanism of this fungus against oxidative stress has not yet been reported. We evaluated the biomass and hypocrellin biosynthesis of Shiraia sp. SUPER-H168
[...] Read more.
Shiraia bambusicola can retain excellent physiological activity when challenged with maximal photo-activated hypocrellin, which causes cellular oxidative stress. The protective mechanism of this fungus against oxidative stress has not yet been reported. We evaluated the biomass and hypocrellin biosynthesis of Shiraia sp. SUPER-H168 when treated with high concentrations of H2O2. Hypocrellin production was improved by nearly 27% and 25% after 72 h incubation with 10 mM and 20 mM H2O2, respectively, while the inhibition ratios of exogenous 20 mM H2O2 on wild S. bambusicola and a hypocrellin-deficient strain were 20% and 33%, respectively. Under exogenous oxidative stress, the specific activities of catalase, glutathione reductase, and superoxide dismutase were significantly increased. These changes may allow Shiraia to maintain normal life activities under oxidative stress. Moreover, sufficient glutathione peroxidase was produced in the SUPER-H168 and hypocrellin-deficient strains, to further ensure that S. bambusicola has excellent protective abilities against oxidative stress. This study creates the possibility that the addition of high H2O2 concentrations can stimulate fungal secondary metabolism, and will lead to a comprehensive and coherent understanding of mechanisms against oxidative stresses from high hydrogen peroxide concentrations in the filamentous fungal Shiraia sp. SUPER-H168. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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Open AccessArticle Activating and Attenuating the Amicoumacin Antibiotics
Molecules 2016, 21(7), 824; doi:10.3390/molecules21070824
Received: 17 March 2016 / Revised: 7 June 2016 / Accepted: 20 June 2016 / Published: 24 June 2016
Cited by 6 | PDF Full-text (4458 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here,
[...] Read more.
The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a “cryptic” amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin’s mode of action was examined through ribosomal structural analyses. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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Open AccessArticle Expression of Terpenoid Biosynthetic Genes and Accumulation of Chemical Constituents in Valeriana fauriei
Molecules 2016, 21(6), 691; doi:10.3390/molecules21060691
Received: 2 April 2016 / Revised: 20 May 2016 / Accepted: 20 May 2016 / Published: 27 May 2016
Cited by 1 | PDF Full-text (1552 KB) | HTML Full-text | XML Full-text
Abstract
Valeriana fauriei (V. fauriei), which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and
[...] Read more.
Valeriana fauriei (V. fauriei), which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR). The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA) and methylerythritol phosphate (MEP) production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS) analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
Open AccessCommunication A Chemo-Enzymatic Road Map to the Synthesis of CoA Esters
Molecules 2016, 21(4), 517; doi:10.3390/molecules21040517
Received: 20 March 2016 / Revised: 11 April 2016 / Accepted: 15 April 2016 / Published: 20 April 2016
Cited by 6 | PDF Full-text (1443 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Coenzyme A (CoA) is a ubiquitous cofactor present in every known organism. The thioesters of CoA are core intermediates in many metabolic processes, such as the citric acid cycle, fatty acid biosynthesis and secondary metabolism, including polyketide biosynthesis. Synthesis of CoA-thioesters is
[...] Read more.
Coenzyme A (CoA) is a ubiquitous cofactor present in every known organism. The thioesters of CoA are core intermediates in many metabolic processes, such as the citric acid cycle, fatty acid biosynthesis and secondary metabolism, including polyketide biosynthesis. Synthesis of CoA-thioesters is vital for the study of CoA-dependent enzymes and pathways, but also as standards for metabolomics studies. In this work we systematically tested five chemo-enzymatic methods for the synthesis of the three most abundant acyl-CoA thioester classes in biology; saturated acyl-CoAs, α,β-unsaturated acyl-CoAs (i.e., enoyl-CoA derivatives), and α-carboxylated acyl-CoAs (i.e., malonyl-CoA derivatives). Additionally we report on the substrate promiscuity of three newly described acyl-CoA dehydrogenases that allow the simple conversion of acyl-CoAs into enoyl-CoAs. With these five methods, we synthesized 26 different CoA-thioesters with a yield of 40% or higher. The CoA esters produced range from short- to long-chain, include branched and α,β-unsaturated representatives as well as other functional groups. Based on our results we provide a general guideline to the optimal synthesis method of a given CoA-thioester in respect to its functional group(s) and the commercial availability of the precursor molecule. The proposed synthetic routes can be performed in small scale and do not require special chemical equipment, making them convenient also for biological laboratories. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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Open AccessArticle Yeast Extract and Silver Nitrate Induce the Expression of Phenylpropanoid Biosynthetic Genes and Induce the Accumulation of Rosmarinic Acid in Agastache rugosa Cell Culture
Molecules 2016, 21(4), 426; doi:10.3390/molecules21040426
Received: 10 January 2016 / Revised: 13 March 2016 / Accepted: 21 March 2016 / Published: 29 March 2016
Cited by 3 | PDF Full-text (3230 KB) | HTML Full-text | XML Full-text
Abstract
The present study aimed to investigate the role of yeast extract and silver nitrate on the enhancement of phenylpropanoid pathway genes and accumulation of rosmarinic acid in Agastache rugosa cell cultures. The treatment of cell cultures with yeast extract (500 mg/L) and silver
[...] Read more.
The present study aimed to investigate the role of yeast extract and silver nitrate on the enhancement of phenylpropanoid pathway genes and accumulation of rosmarinic acid in Agastache rugosa cell cultures. The treatment of cell cultures with yeast extract (500 mg/L) and silver nitrate (30 mg/L) for varying times enhanced the expression of genes in the phenylpropanoid pathway and the production of rosmarinic acid. The results indicated that the expression of RAS and HPPR was proportional to the amount of yeast extract and silver nitrate. The transcript levels of HPPR under yeast extract treatment were 1.84-, 1.97-, and 2.86-fold higher than the control treatments after 3, 6, and 12 h, respectively, whereas PAL expression under silver nitrate treatment was 52.31-fold higher than in the non-treated controls after 24 h of elicitation. The concentration of rosmarinic acid was directly proportional to the concentration of the applied elicitors. Yeast extract supplementation documented the highest amount of rosmarinic acid at 4.98 mg/g, whereas silver nitrate addition resulted in a comparatively lower amount of rosmarinic acid at 0.65 mg/g. In conclusion, addition of yeast extract to the cell cultures enhanced the accumulation of rosmarinic acid, which was evidenced by the expression levels of the phenylpropanoid biosynthetic pathway genes in A. rugosa. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
Open AccessArticle Cloning, Expression Profiling and Functional Analysis of CnHMGS, a Gene Encoding 3-hydroxy-3-Methylglutaryl Coenzyme A Synthase from Chamaemelum nobile
Molecules 2016, 21(3), 316; doi:10.3390/molecules21030316
Received: 24 January 2016 / Revised: 28 February 2016 / Accepted: 2 March 2016 / Published: 8 March 2016
Cited by 2 | PDF Full-text (3302 KB) | HTML Full-text | XML Full-text
Abstract
Roman chamomile (Chamaemelum nobile L.) is renowned for its production of essential oils, which major components are sesquiterpenoids. As the important enzyme in the sesquiterpenoid biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGS) catalyze the crucial step in the mevalonate pathway in plants.
[...] Read more.
Roman chamomile (Chamaemelum nobile L.) is renowned for its production of essential oils, which major components are sesquiterpenoids. As the important enzyme in the sesquiterpenoid biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGS) catalyze the crucial step in the mevalonate pathway in plants. To isolate and identify the functional genes involved in the sesquiterpene biosynthesis of C. nobile L., a HMGS gene designated as CnHMGS (GenBank Accession No. KU529969) was cloned from C. nobile. The cDNA sequence of CnHMGS contained a 1377 bp open reading frame encoding a 458-amino-acid protein. The sequence of the CnHMGS protein was highly homologous to those of HMGS proteins from other plant species. Phylogenetic tree analysis revealed that CnHMGS clustered with the HMGS of Asteraceae in the dicotyledon clade. Further functional complementation of CnHMGS in the mutant yeast strain YSC6274 lacking HMGS activity demonstrated that the cloned CnHMGS cDNA encodes a functional HMGS. Transcript profile analysis indicated that CnHMGS was preferentially expressed in flowers and roots of C. nobile. The expression of CnHMGS could be upregulated by exogenous elicitors, including methyl jasmonate and salicylic acid, suggesting that CnHMGS was elicitor-responsive. The characterization and expression analysis of CnHMGS is helpful to understand the biosynthesis of sesquiterpenoid in C. nobile at the molecular level and also provides molecular wealth for the biotechnological improvement of this important medicinal plant. Full article
(This article belongs to the Special Issue Biosynthesis of Natural Products)
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