Carnivorous Plants as a Source of Potent Bioactive Compound: Naphthoquinones

Carnivorous plants are among the curiosities of nature being different from the normal plants in their mode of nutrition. These plants have fascinated several researchers for centuries. They are also characterized by synthesis of bioactive compounds which are used as a mechanism for self defense. These compounds possess a broad spectrum of biological activities such as antiparasitic, antibacterial, insecticidal, fungicidal, anti-inflammatory, antipyretic, antiproliferative activities. Although, several antimicrobial drugs have been introduced during the recent decades, the problems of microbial infections resistant to synthetic pesticides still exist which necessitate the introduction of novel antimicrobial agents with additional modes of actions than the currently available therapeutic agents. Naphthoquinones are one of the most studied bioactive compounds which have been reported to inhibit the growth of proliferative cells and microbes. Efforts have been made to induce the biosynthesis of naphthoquinone in different species of carnivorous plants. It has been demonstrated that the accumulation of naphthoquinones in carnivorous plants was increased by injecting chitin into the plant tissues. Also, their biosynthesis could be enhanced by the incorporation of elicitors in in vitro cultures of plants. In the present review, we discuss the applications of naphthoquinones and its biosynthesis in carnivorous plants.     

Exploiting the genetic potential of polyketide producing streptomycetes

Streptomycetes are the most important bacterial producers of bioactive secondary metabolites such as antibiotics or cytostatics. Due to the emerging resistance of pathogenic bacteria to all commonly used antibiotics, new and modified natural compounds are required for the development of novel drugs. In addition to the classical screening for natural compounds, genome driven approaches like combinatorial biosynthesis are permanently gaining relevance for the generation of new structures. This technology utilizes the combination of genes from different biosynthesis pathways resulting in the production of novel or modified metabolites. The basis for this strategy is the access to a significant number of genes and the knowledge about the activity and specificity of the enzymes encoded by them. A joint initiative was started to exploit the biosynthesis gene clusters from streptomycetes. In this publication, an overview of the strategy for the identification and characterization of numerous biosynthesis gene clusters for polyketides displaying interesting functions and particular structural features is given.     

Biosynthesis pathways for deoxysugars in antibiotic-producing actinomycetes: isolation, characterization and generation of novel glycosylated derivatives

Many bioactive natural products synthesized by actinomycetes are glycosylated compounds in which the appended sugars contribute to specific interactions with their biological target. Most of these sugars are 6-deoxyhexoses, of which more than 70 different forms have been identified, and an increasing number of gene clusters involved in 6-deoxyhexoses biosynthesis are being characterized from antibiotic-producing actinomycetes. Novel glycosylated compounds have been generated by modifying natural deoxysugar biosynthesis pathways in the producer organisms, and/or the simultaneous expression in these strains of selected deoxysugar biosynthesis genes from other strains. Non-producing strains endowed with the capacity to synthesize novel deoxysugars through the expression of engineered deoxysugar biosynthesis clusters can also be used as alternative hosts. Transfer of these deoxysugars to a multiplicity of aglycones relies upon the existence of glycosyltransferases with an inherent degree of 'relaxed substrate specificity'. In this review, we analyze how the knowledge coming out from isolation and characterization of deoxysugar biosynthesis pathways from actinomycetes is being used to produce novel glycosylated derivatives of natural products.     

Interspecies complementation in Saccharopolyspora erythraea : elucidation of the function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus and generation of new erythromycin derivatives

Two glycosyltransferase genes, oleG1 and oleG2, and a putative isomerase gene, oleP1, have previously been identified in the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus. In order to identify which of these two glycosyltransferases encodes the desosaminyltransferase and which the oleandrosyltransferase, interspecies complementation has been carried out, using two mutant strains of Saccharopolyspora erythraea, one strain carrying an internal deletion in the eryCIII (desosaminyltransferase) gene and the other an internal deletion in the eryBV (mycarosyltransferase) gene. Expression of the oleG1 gene in the eryCIII deletion mutant restored the production of erythromycin A (although at a low level), demonstrating that oleG1 encodes the desosaminyltransferase required for the biosynthesis of oleandomycin and indicating that, as in erythromycin biosynthesis, the neutral sugar is transferred before the aminosugar onto the macrocyclic ring. Significantly, when an intact oleG2 gene (presumed to encode the oleandrosyltransferase) was expressed in the eryBV deletion mutant, antibiotic activity was also restored and, in addition to erythromycin A, new bioactive compounds were produced with a good yield. The neutral sugar residue present in these compounds was identified as L-rhamnose attached at position C-3 of an erythronolide B or a 6-deoxyerythronolide B lactone ring, thus indicating a relaxed specificity of the oleandrosyltransferase, OleG2, for both the activated sugar and the macrolactone substrate. The oleP1 gene located immediately upstream of oleG1 was likewise introduced into an eryCII deletion mutant of Sac. erythraea, and production of erythromycin A was again restored, demonstrating that the function of OleP1 is identical to that of EryCII in the biosynthesis of dTDP-D-desosamine, which we have previously proposed to be a dTDP-4-keto-6-deoxy-D-glucose 3, 4-isomerase.     

链霉菌来源的苯并异色烷醌家族抗生素的生物合成

苯并异色烷醌(benzoisochromanequinones,BIQs)家族抗生素是由链霉菌产生的聚酮类抗生素,其芳香聚酮母核结构中含有并联的两个芳香环和一个吡喃环,具有抗菌、抗肿瘤等多种生物学活性。BIQ抗生素聚酮链的早期生物合成过程代表了芳香聚酮抗生素母核的典型合成机制,而不同的后期修饰则决定了它们结构和生物学活性的多样性。在过去的二十几年中,以放线紫红素和美达霉素为研究重点,BIQ家族抗生素的生物合成机制逐渐得到揭示,但在后期结构修饰方面仍有许多问题有待解决。本文对BIQ家族抗生素的生物合成机制研究进行了综述,比较了不同BIQ家族抗生素结构特点、生物学活性,并重点阐述了它们生物合成中的后期结构修饰和调控过程的研究进展,并对BIQ抗生素在代谢工程方面的研究进行了展望。     

Die Toxine der Cyanobakterien: Neue bioaktive Verbindungen

Cyanobacteria produce numerous bioactive compounds including potent neuro‐ and hepatotoxins. The genes for the biosynthesis of microcystin, a hepatotoxic, cyclic heptapeptide, have been identified. Sequence analysis of these genes revealed that cyanobacteria ossess, like some other bacteria and lower eukaryotes, giant protein complexes consisting of peptide synthetases, olyketide synthases and tayloring enzymes involved in the biosynthesis of nonribosomal peptides and polyketides. Cyanobacteria represent a rich source of modules and domaines for the molecular design of new enzymes for the synthesis of bioactive compounds.     

Polyene antibiotic biosynthesis gene clusters

Over the past 15 years the biosynthetic gene clusters for numerous bioactive polyketides have been intensively studied and recently this work has been extended to the antifungal polyene macrolides. These compounds consist of large macrolactone rings that have a characteristic series of conjugated double bonds, as well as an exocyclic carboxyl group and an unusual mycosamine sugar. The biosynthetic gene clusters for nystatin, pimaricin, amphotericin and candicidin have been investigated in detail. These clusters contain the largest modular polyketide synthase genes reported to date. This body of work also provides insights into the enzymes catalysing the unusual post-polyketide modifications, and the genes regulating antibiotic biosynthesis. The sequences also provide clues about the evolutionary origins of polyene biosynthetic genes. Successful genetic manipulation of the producing organisms leading to production of polyene analogues indicates good prospects for generating improved antifungal compounds via genetic engineering.     

Bioactive natural products from marine cyanobacteria for drug discovery

The prokaryotic marine cyanobacteria continue to be an important source of structurally bioactive secondary metabolites. A majority of these molecules are nitrogen-containing compounds biosynthesized by large multimodular nonribosomal polypeptide (NRP) or mixed polyketide-NRP enzymatic systems. A total of 128 marine cyanobacterial alkaloids, published in the literature between January 2001 and December 2006, are presented in this review with emphasis on their biosynthesis and biological activities. In addition, a number of highly cytotoxic compounds such as hectochlorin, lyngbyabellins, apratoxins, and aurilides have been identified as potential lead compounds for the development of anticancer agents. A brief coverage on the distribution of natural product biosynthetic genes as well as the mechanisms of tailoring enzymes involved in the biosynthesis of cyanobacterial compounds will also be given.     

Photoprotective compounds from marine organisms

The substantial loss in the stratospheric ozone layer and consequent increase in solar ultraviolet radiation on the earth’s surface have augmented the interest in searching for natural photoprotective compounds in organisms of marine as well as freshwater ecosystems. A number of photoprotective compounds such as mycosporine-like amino acids (MAAs), scytonemin, carotenoids and several other UV-absorbing substances of unknown chemical structure have been identified from different organisms. MAAs form the most common class of UV-absorbing compounds known to occur widely in various marine organisms; however, several compounds having UV-screening properties still need to be identified. The synthesis of scytonemin, a predominant UV-A-photoprotective pigment, is exclusively reported in cyanobacteria. Carotenoids are important components of the photosynthetic apparatus that serve both light-harvesting and photoprotective functions, either by direct quenching of the singlet oxygen or other toxic reactive oxygen species or by dissipating the excess energy in the photosynthetic apparatus. The production of photoprotective compounds is affected by several environmental factors such as different wavelengths of UVR, desiccation, nutrients, salt concentration, light as well as dark period, and still there is controversy about the biosynthesis of various photoprotective compounds. Recent studies have focused on marine organisms as a source of natural bioactive molecules having a photoprotective role, their biosynthesis and commercial application. However, there is a need for extensive work to explore the photoprotective role of various UV-absorbing compounds from marine habitats so that a range of biotechnological and pharmaceutical applications can be found.     

Bioactive Natural Products from Papua New Guinea Marine Sponges

The discovery of novel natural products for drug development relies heavily upon a rich biodiversity, of which the marine environment is an obvious example. Marine natural product research has spawned several drugs and many other candidates, some of which are the focus of current clinical trials. The sponge megadiversity of Papua New Guinea is a rich but underexplored source of bioactive natural products. Here, we review some of the many natural products derived from PNG sponges with an emphasis on those with interesting biological activity and, therefore, drug potential. Many bioactive natural products discussed here appear to be derived from non‐ribosomal peptide and polyketide biosynthesis pathways, strongly suggesting a microbial origin of these compounds. With this in mind, we also explore the notion of sponge‐symbiont biosynthesis of these bioactive compounds and present examples to support the working hypothesis.     

Biosynthesis of phenolic compounds and its regulation in apple

This paper summarises the information on the occurrence of phenolic compounds in apple Malus domestica leaves and fruits with special reference to their developmental changes and regulation of biosynthesis. Besides the ontogenetic variation in biosynthesis and accumulation, the stress-induced and pathogenesis-related changes are emphasised. Aspects of commercial importance are addressed, ranging from fruit colouration, through disease resistance, to the direct use of apple tissues, as raw material for the extraction of bioactive phenolic compounds.     

Generation of hybrid elloramycin analogs by combinatorial biosynthesis using genes from anthracycline-type and macrolide biosynthetic pathways

Elloramycin and oleandomycin are two polyketide compounds produced by Streptomyces olivaceus Tü2353 and Streptomyces antibioticus ATCC11891, respectively. Elloramycin is an anthracycline-like antitumor drug and oleandomycin a macrolide antibiotic. Expression in S. albus of a cosmid (cos16F4) containing part of the elloramycin biosynthetic gene cluster produced the elloramycin non-glycosylated intermediate 8-demethyl-tetracenomycin C. Several plasmid constructs harboring different gene combinations of L-oleandrose (neutral 2,6-dideoxyhexose attached to the macrolide antibiotic oleandomycin) biosynthetic genes of S. antibioticus that direct the biosynthesis of L-olivose, L-oleandrose and L-rhamnose were coexpressed with cos16F4 in S. albus. Three new hybrid elloramycin analogs were produced by these recombinant strains through combinatorial biosynthesis, containing elloramycinone or 12a-demethyl-elloramycinone (= 8-demethyl-tetracenomycin C) as aglycone moiety encoded by S. olivaceus genes and different sugar moieties, coded by the S. antibioticus genes. Among them is L-olivose, which is here described for the first time as a sugar moiety of a natural product.     

Ganoderma lucidum: A potential pleiotropic approach of ganoderic acids in health reinforcement and factors influencing their production

Ganoderma lucidum (G. lucidum) main attractive pharmacological characteristics are antitumor and immunomodulatory activities which are chiefly associated with its two principal bioactive compounds, those are polysaccharides and triterpenoids. Ganoderic acids (GAs) are one of the most discovered triterpenoids of G. lucidum among various triterpenoids. The prominent medicinal mushroom G. lucidum possesses GAs as essential bioactive constituents that are highly oxygenated lanostane-type triterpenoids. GAs exhibit diverse potential action against numerous diseases such as anticancer, antioxidant, anti-inflammatory, anti-HIV, cardioprotective, antiallergic, antihepatotoxic, neuroprotective and antinociceptive properties. GAs act through different mechanisms that include cytotoxic, apoptosis, inducing cell cycle arrest, inhibition of topoisomerases, antiproliferation, anti-invasion, inhibition of NF-kB AP1/uPA, farnesyl protein transferase and JAK-STAT3 pathway. The miraculous effects of GAs fascinate the researchers for their production. Various environmental factors such as biochemical signals, nutritional and physical that influence the biosynthesis of GA. However, the scarcities of pure compounds or accurately characterized extracts are the main problem of clinical studies. Substantial steps are required for characterized extracts of active compounds. This review contributes a thorough insight into the mode of actions of GAs and their possible reinforcements to overcome various diseases.     

宏基因组文库技术获得聚酮化合物

聚酮化合物是一类重要的具有生物活性的次级代谢物。由于运用传统方法从自然界中直接筛选新型天然聚酮化合物的重现率很高, 近年来出现了很多开发新型聚酮化合物的新方法, 文章主要介绍通过环境宏基因组文库获得新聚酮类化合物的方法。     

Bioactive compounds synthesized by non-ribosomal peptide synthetases and type-I polyketide synthases discovered through genome-mining and metagenomics

Non-ribosomal peptide synthetases (NRPS) and type-I polyketide synthases (PKS-I) are multimodular enzymes involved in biosynthesis of oligopeptide and polyketide secondary metabolites produced by microorganisms such as bacteria and fungi. New findings regarding the mechanisms underlying NRPS and PKS-I evolution illustrate how microorganisms expand their metabolic potential. During the last decade rapid development of bioinformatics tools as well as improved sequencing and annotation of microbial genomes led to discovery of novel bioactive compounds synthesized by NRPS and PKS-I through genome-mining. Taking advantage of these technological developments metagenomics is a fast growing research field which directly studies microbial genomes or specific gene groups and their products. Discovery of novel bioactive compounds synthesized by NRPS and PKS-I will certainly be accelerated through metagenomics, allowing the exploitation of so far untapped microbial resources in biotechnology and medicine.     

Flesh Color Diversity of Sweet Potato: An Overview of the Composition,Functions, Biosynthesis,and Gene Regulation of the Major Pigments

Sweet potato is a multifunctional root crop and a source of food with many essential nutrients and bioactive compounds. Variations in the flesh color of the diverse sweet potato varieties are attributed to the different phytochemicals and natural pigments they produce. Among them, carotenoids and anthocyanins are the main pigments known for their antioxidant properties which provide a host of health benefits, hence, regarded as a major component of the human diet. In this review, we provide an overview of the major pigments in sweet potato with much emphasis on their biosynthesis, functions, and regulatory control. Moreover, current findings on the molecular mechanisms underlying the biosynthesis and accumulation of carotenoids and anthocyanins in sweet potato are discussed. Insights into the composition, biosynthesis, and regulatory control of these major pigments will further advance the biofortification of sweet potato and provide a reference for breeding carotenoid- and anthocyanin-rich varieties.     

Tailoring modification of deoxysugars during biosynthesis of the antitumour drug chromomycin A by Streptomyces griseus ssp. griseus

Chromomycin A3 is a member of the aureolic acid group family of antitumour drugs. Three tailoring modification steps occur during its biosynthesis affecting the sugar moieties: two O-acetylations and one O-methylation. The 4-O-methylation in the 4-O-methyl-D-oliose moiety of the disaccharide chain is catalysed by the cmmMIII gene product. Inactivation of this gene generated a chromomycin-non-producing mutant that accumulated three unmethylated derivatives containing all sugars but differing in the acylation pattern. Two of these compounds were shown to be substrates of the methyltransferase as determined by their bioconversion into chromomycin A2 and A3 after feeding these compounds to a Streptomyces albus strain expressing the cmmMIII gene. The same single membrane-bound enzyme, encoded by the cmmA gene, is responsible for both acetyl transfer reactions, which convert a relatively inactive compound into the bioactive chromomycin A3. Insertional inactivation of this gene resulted in a mutant accumulating a dideacetylated chromomycin A3 derivative. This compound, lacking both acetyl groups, was converted in a two-step reaction via the 4E-monoacetylated intermediate into chromomycin A3 when fed to cultures of S. albus expressing the cmmA gene. This acetylation step would occur as the last step in chromomycin biosynthesis, being a very important event for self-protection of the producing organism. It would convert a molecule with low biological activity into an active one, in a reaction catalysed by an enzyme that is predicted to be located in the cell membrane.     

NMR metabolomics of berry quality in sea buckthorn (Hippophae L.)

Sea buckthorn (Hippophae L.) is a woody perennial shrub or small tree whose berries are rich in bioactive compounds with powerful nutritional and medicinal properties. Untargeted ¹H nuclear magnetic resonance (NMR) spectroscopy and principal component analysis (PCA) were used to characterize the metabolic profile of berry quality. There was strong separation in the NMR signal intensity of bioactive compounds between pulp and seeds, such as amino acids [gamma-aminobutyric acid (GABA), aspartate, glutamate, theanine, and proline], organic acids (citrate, succinate, malate, acetate, quinate, and heriguard), and carbohydrates (sucrose, fructose, glucose, and melibiose). Sea buckthorn cultivars could be clearly separated into two groups using principal component analysis (PCA) based on NMR spectroscopy of bioactive compounds in the pulp and seeds. Several metabolic compounds such as sugar, organic acids, and amino acids could serve as biomarkers for prediction of berry quality and for classification of germplasm collections. This dataset provides potential information concerning the mechanisms of berry quality formation and contributes to increasing the breeding efficiency of sea buckthorn quality improvement.