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Covering: up to 2021Plants and their associated microbial communities are known to produce millions of metabolites, a majority of which are still not characterized and are speculated to possess novel bioactive properties. In addition to their role in plant physiology, these metabolites are also relevant as existing and next-generation medicine candidates. Elucidation of the plant metabolite diversity is thus valuable for the successful exploitation of natural resources for humankind. Herein, we present a comprehensive review on recent metabolomics approaches to illuminate molecular networks in plants, including chemical isolation and enzymatic production as well as the modern metabolomics approaches such as stable isotope labeling, ultrahigh-resolution mass spectrometry, metabolome imaging (spatial metabolomics), single-cell analysis, cheminformatics, and computational mass spectrometry. Mass spectrometry-based strategies to characterize plant metabolomes through metabolite identification and annotation are described in detail. We also highlight the use of phytochemical genomics to mine genes associated with specialized metabolites' biosynthesis. Understanding the metabolic diversity through biotechnological advances is fundamental to elucidate the functions of the plant-derived specialized metabolome.

Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these naturally produced nitrogenous compounds to combat numerous challenging environmental stress conditions. Traditional and modern healthcare systems have harnessed the potential of these organic compounds for the treatment of many ailments. Various chemical entities (functional groups) attached to the central moiety are responsible for their diverse range of biological properties. The development of the characterization of these plant metabolites and the enzymes involved in their biosynthesis is of an utmost priority to deliver enhanced advantages in terms of biological properties and productivity. Further, the incorporation of whole/partial metabolic pathways in the heterologous system and/or the overexpression of biosynthetic steps in homologous systems have both become alternative and lucrative methods over chemical synthesis in recent times. Moreover, in-depth research on alkaloid biosynthetic pathways has revealed numerous chemical modifications that occur during alkaloidal conversions. These chemical reactions involve glycosylation, acylation, reduction, oxidation, and methylation steps, and they are usually responsible for conferring the biological activities possessed by alkaloids. In this review, we aim to discuss the alkaloidal group of plant specialized metabolites and their brief classification covering major categories. We also emphasize the diversity in the basic structures of plant alkaloids arising through enzymatically catalyzed structural modifications in certain plant species, as well as their emerging diverse biological activities. The role of alkaloids in plant defense and their mechanisms of action are also briefly discussed. Moreover, the commercial utilization of plant alkaloids in the marketplace displaying various applications has been enumerated.

Plants are rich in phytoconstituent biomolecules that served as a good source of medicine. More recently, they have been employed in synthesizing metal/metal oxide nanoparticles (NPs) due to their capping and reducing properties. This green synthesis approach is environmentally friendly and allows the production of the desired NPs in different sizes and shapes by manipulating parameters during the synthesis process. The most commonly used metals and oxides are gold (Au), silver (Ag), and copper (Cu). Among these, Cu is a relatively low-cost metal that is more cost-effective than Au and Ag. In this review, we present an overview and current update of plant-mediated Cu/copper oxide (CuO) NPs, including their synthesis, medicinal applications, and mechanisms. Furthermore, the toxic effects of these NPs and their efficacy compared to commercial NPs are reviewed. This review provides an insight into the potential of developing plant-based Cu/CuO NPs as a therapeutic agent for various diseases in the future.

Plants synthesize a large number of natural products, many of which are bioactive and have practical values as well as commercial potential. To explore this vast structural diversity, we present PSC-db, a unique plant metabolite database aimed to categorize the diverse phytochemical space by providing 3D-structural information along with physicochemical and pharmaceutical properties of the most relevant natural products. PSC-db may be utilized, for example, in qualitative estimation of biological activities (Quantitative Structure-Activity Relationship, QSAR) or massive docking campaigns to identify new bioactive compounds, as well as potential binding sites in target proteins. PSC-db has been implemented using the open-source PostgreSQL database platform where all compounds with their complementary and calculated information (classification, redundant names, unique IDs, physicochemical properties, etc.) were hierarchically organized. The source organism for each compound, as well as its biological activities against protein targets, cell lines and different organism were also included. PSC-db is freely available for public use and is hosted at the Universidad de Talca.

Non-nutritive phytochemicals (secondary metabolites and fibre) can influence plant resistance to herbivores and have ecological impacts on animal and plant population dynamics. A major hindrance to the ecological study of these phytochemicals is the uncertainty in the compounds one should measure, especially when limited by cost and expertise. With the underlying goal of identifying proxies of plant resistance to herbivores, we performed a systematic review of the effects of non-nutritive phytochemicals on consumption by leporids (rabbits and hares) and cervids (deer family). We identified 133 out of 1790 articles that fit our selection criteria (leporids = 33, cervids = 97, both herbivore types = 3). These articles cover 18 species of herbivores, on four continents. The most prevalent group of phytochemicals in the selected articles was phenolics, followed by terpenes for leporids and by fibre for cervids. In general, the results were variable but phenolic concentration seems linked with high resistance to both types of herbivores. Terpene concentration is also linked to high plant resistance; this relationship seems driven by total terpene content for cervids and specific terpenes for leporids. Tannins and fibre did not have a consistent positive effect on plant resistance. Because of the high variability in results reported and the synergistic effects of phytochemicals, we propose that the choice of chemical analyses must be tightly tailored to research objectives. While researchers pursuing ecological or evolutionary objectives should consider multiple specific analyses, researchers in applied studies could focus on a fewer number of specific analyses. An improved consideration of plant defence, based on meaningful chemical analyses, could improve studies of plant resistance and allow us to predict novel or changing plant-herbivore interactions.

Plants produce a myriad of structurally and functionally diverse metabolites that play many different roles in plant growth and development and in plant response to continually changing environmental conditions as well as abiotic and biotic stresses. This metabolic diversity is, to a large extent, due to chemical modification of the basic skeletons of metabolites. Here, we review the major known plant metabolite modifications and summarize the progress that has been achieved and the challenges we are facing in the field. We focus on discussing both technical and functional aspects in studying the influences that various modifications have on biosynthesis, degradation, transport, and storage of metabolites, as well as their bioactivity and toxicity. Finally, we discuss some emerging insights into the evolution of metabolic pathways and metabolite functionality., (Copyright © 2019 The Author. Published by Elsevier Inc. All rights reserved.)

Covering: up to 2018 Plants are sessile organisms. To compensate for not being able to escape when challenged by unfavorable growth conditions, pests or herbivores, plants have perfected their metabolic plasticity by having developed the capacity for on demand synthesis of a plethora of phytochemicals to specifically respond to the challenges arising during plant ontogeny. Key steps in the biosynthesis of phytochemicals are catalyzed by membrane-bound cytochrome P450 enzymes which in plants constitute a superfamily. In planta, the P450s may be organized in dynamic enzyme clusters (metabolons) and the genes encoding the P450s and other enzymes in a specific pathway may be clustered. Metabolon formation facilitates transfer of substrates between sequential enzymes and therefore enables the plant to channel the flux of general metabolites towards biosynthesis of specific phytochemicals. In the plant cell, compartmentalization of the operation of specific biosynthetic pathways in specialized plastids serves to avoid undesired metabolic cross-talk and offers distinct storage sites for molar concentrations of specific phytochemicals. Liquid-liquid phase separation may lead to formation of dense biomolecular condensates within the cytoplasm or vacuole allowing swift activation of the stored phytochemicals as required upon pest or herbivore attack. The molecular grid behind plant plasticity offers an endless reservoir of functional modules, which may be utilized as a synthetic biology tool-box for engineering of novel biological systems based on rational design principles. In this review, we highlight some of the concepts used by plants to coordinate biosynthesis and storage of phytochemicals.

Covering: 2006 to 2018 Phytochemicals are important sources for the discovery and development of agricultural and pharmaceutical compounds, such as pesticides and medicines. However, these compounds are typically present in low abundance in nature, and the biosynthetic pathways for most phytochemicals are not fully elucidated. Heterologous production of phytochemicals in plant, bacterial, and yeast hosts has been pursued as a potential approach to address sourcing issues associated with many valuable phytochemicals, and more recently has been utilized as a tool to aid in the elucidation of plant biosynthetic pathways. Due to the structural complexity of certain phytochemicals and the associated biosynthetic pathways, reconstitution of plant pathways in heterologous hosts can encounter numerous challenges. Synthetic biology approaches have been developed to address these challenges in areas such as precise control over heterologous gene expression, improving functional expression of heterologous enzymes, and modifying central metabolism to increase the supply of precursor compounds into the pathway. These strategies have been applied to advance plant pathway reconstitution and phytochemical production in a wide variety of heterologous hosts. Here, we review synthetic biology strategies that have been recently applied to advance complex phytochemical production in heterologous hosts.

Polyphenols are bioactives claimed to be responsible for some of the health benefits provided by fruit and vegetables. It is currently accepted that the bioactivities of polyphenols can be mostly ascribed to their interactions with proteins and lipids. Such interactions can affect cell oxidant production and cell signaling, and explain in part the ability of polyphenols to promote health. EC can modulate redox sensitive signaling by: i) defining the extent of oxidant levels that can modify cell signaling, function, and fate, e.g. regulating enzymes that generate superoxide, hydrogen peroxide and nitric oxide; or ii) regulating the activation of transcription factors sensible to oxidants. The latter includes the regulation of the nuclear factor E2-related factor 2 (Nfr2) pathway, which in turn can promote the synthesis of antioxidant defenses, and of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway, which mediates the expression of oxidants generating enzymes, as well as proteins not involved in redox reactions. In summary, a significant amount of data vindicates the participation of EC in redox regulated signaling pathways. Progress in the understanding of the molecular mechanisms involved in EC biological actions will help to define recommendations in terms of which fruit and vegetables are healthier and the amounts necessary to provide health effects., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Even though lactic acid bacteria are only a small part of the plant autochthonous microbiota, they represent the most important microbes having the capability to promote significant changes in the health-promoting properties of plant foods. Owing to the variety of plant chemical components and the possible pathways for bioconversion, plant fermentation is like a metabolic labyrinth undertaken by bacteria. The winding metabolic pathways involve several secondary plant metabolites (e.g. phenolics). The success of these paths is connected to the adaptive growth and survival of lactic acid bacteria. A panel of various interacting omics approaches unraveled the specific traits of lactic acid bacteria to adapt to plants, which allow the optimal design of fermentation strategies for targeted raw matrices., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Nanoscale iron particles have attracted substantial interest due to their unique physical and chemical properties. Over the years, various physical and chemical methods have been developed to synthesize these nanostructures which are usually expensive and potentially harmful to human health and the environment. Synthesis of iron nanoparticles (INPs) by using plant extract is now of great interest in order to develop a novel and sustainable approach toward green chemistry. In this method the chemical compounds and organic solvents are replaced with phytochemicals and aqueous matrixes, respectively. Similar to any chemical and biochemical reaction, factors such as reaction temperature, concentration of iron precursor, concentration of leaf extract, and reaction time have critical effects on the reaction yield. This review focuses on the novel approaches used for green synthesis of INPs by using plant resources. The currently available statistics including the factors affecting the synthesis process and potential applications of the fabricated nanoparticles are discussed. Recommendations are also given for areas of future research in order to improve the production process.

Plants respond to herbivore attack by launching 2 types of defenses: direct defense and indirect defense. Direct defense includes all plant traits that increase the resistance of host plants to insect herbivores by affecting the physiology and/or behavior of the attackers. Indirect defense includes all traits that by themselves do not have significant direct impact on the attacking herbivores, but can attract natural enemies of the herbivores and thus reduce plant loss. When plants recognize herbivore-associated elicitors, they produce and release a blend of volatiles that can attract predators, parasites, and other natural enemies. Known herbivore-associated elicitors include fatty acid-amino acid conjugates, sulfur-containing fatty acids, fragments of cell walls, peptides, esters, and enzymes. Identified plant volatiles include terpenes, nitrogenous compounds, and indoles. In addition, constitive traits including extrafloral nectars, food bodies, and domatia can be further induced to higher levels and attract natural enemies as well as provide food and shelter to carnivores. A better understanding of indirect plant defense at global and componential levels via advanced high throughput technologies may lead to utilization of indirect defense in suppression of herbivore damage to plants., (© 2016 Institute of Zoology, Chinese Academy of Sciences.)

Light-emitting diode (LED) lighting technology with narrow-bandwidth illumination helps to reduce energy consumption on covered crops. Here, we discuss how this new technology, which provides flexible modification of light spectra, will open new avenues for natural modulation of medicinal and crop plant metabolomes for better colour, flavour, fragrance, and antioxidant properties., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Based on available literature, ecology and economy of light emitting diode (LED) lights in plant foods production were assessed and compared to high pressure sodium (HPS) and compact fluorescent light (CFL) lamps. The assessment summarises that LEDs are superior compared to other lamp types. LEDs are ideal in luminous efficiency, life span and electricity usage. Mercury, carbon dioxide and heat emissions are also lowest in comparison to HPS and CFL lamps. This indicates that LEDs are indeed economic and eco-friendly lighting devices. The present review indicates also that LEDs have many practical benefits compared to other lamp types. In addition, they are applicable in many purposes in plant foods production. The main focus of the review is the targeted use of LEDs in order to enrich phytochemicals in plants. This is an expedient to massive improvement in production efficiency, since it diminishes the number of plants per phytochemical unit. Consequently, any other production costs (e.g. growing space, water, nutrient and transport) may be reduced markedly. Finally, 24 research articles published between 2013 and 2017 were reviewed for targeted use of LEDs in the specific, i.e. blue range (400-500 nm) of spectrum. The articles indicate that blue light is efficient in enhancing the accumulation of health beneficial phytochemicals in various species. The finding is important for global food production. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

The chromatographic behavior of 28 plant secondary metabolites belonging to four chemically similar classes (alkaloids, flavonoids, flavone glycosides and sesquiterpenes) was studied by normal-phase thin-layer chromatography (NP-TLC) under 5 different chromatographic systems commonly used in plant drug analysis with the aim to explore whether the retention properties of these metabolites can determine the chemical group they belong to. The use of RM values as the retention parameter is implemented as a relatively new approach in plant analysis. Principal component analysis (PCA), hierarchical clustering heat maps and discriminant analysis (DA), were used for statistical evaluation of the chromatographic data and extraction of similarities between chemically related compounds. The twenty eight metabolites were classified into four groups by principal component analysis. The heat map of hierarchical clustering revealed that all metabolites were clustered into four groups, except for caffeine, while linear discriminant analysis showed that 96.4% of metabolites are predicted correctly as the groupings identified by chemical class in original and cross-validated data. The main advantage of the approach described in current paper is its simplicity which can assist with preliminary identification of metabolites in complex plant extracts., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Humans can ingest gram amounts of plant secondary metabolites daily through diet. Many of these phytochemicals are bioactive beyond our current understanding because they act through weak negative biological feedback mechanisms, undetectable in vitro. Homeostatic-type assessments shed light on the evolutionary implications of the human diet from plants, giving rise to the metabolic plant feedback hypothesis. The hypothesis states that ancient diets rich in carbohydrates coincide with bulk dietary phytochemicals that act as nonspecific inhibitors of metabolic and inflammatory processes. Consequently, food-derived phytochemicals are likely to be equally effective as herbal medicines for these indications. In addition to the ubiquitous flavonoids, terpenoids, and fatty acids in the diet, the likely impact of chronic chlorophyll ingestion on human health is discussed, and data on its modulation of blood glucose levels are presented. A major deduction of this hypothesis is that starchy diets lacking plant secondary metabolites are associated with multimorbidity (lifestyle diseases) including obesity, type 2 diabetes, and cardiovascular disease. It is proposed that the intake of leafy vegetables, spices, and herbal remedies rich in phytochemicals matches the transition and genetic adaptation to early agriculture, playing a compensatory role in the mismatch of old genes and new diets., (Georg Thieme Verlag KG Stuttgart · New York.)

Selenium is naturally present in soils but it is also produced by pollution from human activities into the environment. Its incorporation into plants affords organoselenium metabolites that, depending on the nature of the molecules and the plant species, can be incorporated into proteins, stored or eliminated by volatilization. The possibility to use the selenium metabolism of some plants as a method for bioremediation and, at the main time, as a source of selenated phytochemicals is here discussed taking into consideration the growing interest in organic selenium derivatives as new potential therapeutic agents.

Hsp90 is an evolutionarily conserved adenosine triphosphate-dependent molecular chaperone and is one of the most abundant proteins in the cells (1-3 %). Hsp90 is induced when a cell undergoes various types of environmental stresses such as heat, cold, or oxygen deprivation. It is involved in the turnover, trafficking, and activity of client proteins, including apoptotic factors, protein kinases, transcription factors, signaling proteins, and a number of oncoproteins. Most of the Hsp90 client proteins are involved in cell growth, differentiation, and survival, and include kinases, nuclear hormone receptors, transcription factors, and other proteins associated with almost all the hallmarks of cancer. Consistent with these diverse activities, genetic and biochemical studies have demonstrated the implication of Hsp90 in a range of diseases, including cancer, making this chaperone an interesting target for drug research.During the last few decades, plant secondary metabolites have been studied as a major source for lead compounds in drug discovery. Recently, several plant-derived small molecules have been discovered exhibiting inhibitory activity towards Hsp90, such as epigallocatechin gallate, gedunin, lentiginosine, celastrol, and deguelin. In this work, an overview of plant secondary metabolites interfering with Hsp90 activities is provided., (Georg Thieme Verlag KG Stuttgart · New York.)

What are the ecological causes and consequences of variation in phytochemical diversity within and between plant taxa? Despite decades of natural products discovery by organic chemists and research by chemical ecologists, our understanding of phytochemically mediated ecological processes in natural communities has been restricted to studies of either broad classes of compounds or a small number of well-characterized molecules. Until now, no studies have assessed the ecological causes or consequences of rigorously quantified phytochemical diversity across taxa in natural systems. Consequently, hypotheses that attempt to explain variation in phytochemical diversity among plants remain largely untested. We use spectral data from crude plant extracts to characterize phytochemical diversity in a suite of co-occurring plants in the tropical genus Piper (Piperaceae). In combination with 20 years of data focused on Piper-associated insects, we find that phytochemical diversity has a direct and positive effect on the diversity of herbivores but also reduces overall herbivore damage. Elevated chemical diversity is associated with more specialized assemblages of herbivores, and the cascading positive effect of phytochemistry on herbivore enemies is stronger as herbivore diet breadth narrows. These results are consistent with traditional hypotheses that predict positive associations between plant chemical diversity, insect herbivore diversity, and trophic specialization. It is clear from these results that high phytochemical diversity not only enhances the diversity of plant-associated insects but also contributes to the ecological predominance of specialized insect herbivores.

Endophytic fungi are those that live internally in apparently healthy and asymptomatic hosts. Endophytic fungi appear to be ubiquitous; indeed, no study has yet shown the existence of a plant species without endophytes. High species diversity is another characteristic of endophytic mycobiota which is depicted by the fact that it is quite common for endophyte surveys to find assemblages consisting of more than 30 fungal species per host plant species. Medicinal plants had been used to isolate and characterize directly the bioactive metabolites. However, the discovery of fungal endophytes inside these plants with capacity to produce the same compounds shifted the focus of new drug sources from plants to fungi. Bioactive natural products from endophytic fungi, isolated from different plant species, are attracting considerable attention from natural product chemists and biologists alike which is clearly depicted by the steady increase of publications devoted to this topic during the recent years. This review will highlight the chemical potential of endophytic fungi with focus on the detection of pharmaceutically valuable plant constituents as products of fungal biosynthesis. In addition, it will cover newly discovered endophytic fungi and also new bioactive metabolites reported in recent years from fungal endophytes. It summarizes the up-to-date and comprehensive information on bioactive compounds from endophytic fungi by having done a thorough survey of literature., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Plant secondary metabolites carry out numerous functions in interactions between plants and a broad range of other organisms. Experimental evidence strongly supports the indispensable contribution of many constitutive and pathogen-inducible phytochemicals to plant innate immunity. Extensive studies on model plant species, particularly Arabidopsis thaliana, have brought significant advances in our understanding of the molecular mechanisms underpinning pathogen-triggered biosynthesis and activation of defensive secondary metabolites. However, despite the proven significance of secondary metabolites in plant response to pathogenic microorganisms, little is known about the precise mechanisms underlying their contribution to plant immunity. This insufficiency concerns information on the dynamics of cellular and subcellular localization of defensive phytochemicals during the encounters with microbial pathogens and precise knowledge on their mode of action. As many secondary metabolites are characterized by their in vitro antimicrobial activity, these compounds were commonly considered to function in plant defense as in planta antibiotics. Strikingly, recent experimental evidence suggests that at least some of these compounds alternatively may be involved in controlling several immune responses that are evolutionarily conserved in the plant kingdom, including callose deposition and programmed cell death., (© 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.)

L-Proline is a widely used compatible solute and is employed by Bacillus subtilis, through both synthesis and uptake, as an osmostress protectant. Here, we assessed the stress-protective potential of the plant-derived L-proline derivatives N-methyl-L-proline, L-proline betaine (stachydrine), trans-4-L-hydroxproline and trans-4-hydroxy-L-proline betaine (betonicine) for cells challenged by high salinity or extremes in growth temperature. l-Proline betaine and betonicine conferred salt stress protection, but trans-4-L-hydroxyproline and N-methyl-L-proline was unable to do so. Except for L-proline, none of these compounds served as a nutrient for B. subtilis. L-Proline betaine was a considerably better osmostress protectant than betonicine, and its import strongly reduced the l-proline pool produced by B. subtilis under osmotic stress conditions, whereas a supply of betonicine affected the L-proline pool only modestly. Both compounds downregulated the transcription of the osmotically inducible opuA operon, albeit to different extents. Mutant studies revealed that L-proline betaine was taken up via the ATP-binding cassette transporters OpuA and OpuC, and the betaine-choline-carnitine-transporter-type carrier OpuD; betonicine was imported only through OpuA and OpuC. L-Proline betaine and betonicine also served as temperature stress protectants. A striking difference between these chemically closely related compounds was observed: L-proline betaine was an excellent cold stress protectant, but did not provide heat stress protection, whereas the reverse was true for betonicine. Both compounds were primarily imported in temperature-challenged cells via the high-capacity OpuA transporter. We developed an in silico model for the OpuAC-betonicine complex based on the crystal structure of the OpuAC solute receptor complexed with L-proline betaine., (The Authors.)

Fresh fruits and vegetables are largely investigated for their content in vitamins, mineral nutrients, dietary fibers, and plant secondary metabolites, collectively called phytochemicals, which play a beneficial role in human health. Quantity and quality of phytochemicals may be detected by using different analytical techniques, providing accurate quantification and identification of single molecules, along with their molecular structures, and allowing metabolome analyses of plant-based foods. Phytochemicals concentration and profiles are affected by biotic and abiotic factors linked to plant genotype, crop management, harvest season, soil quality, available nutrients, light, and water. Soil health and biological fertility play a key role in the production of safe plant foods, as a result of the action of beneficial soil microorganisms, in particular of the root symbionts arbuscular mycorrhizal fungi. They improve plant nutrition and health and induce changes in secondary metabolism leading to enhanced biosynthesis of health-promoting phytochemicals, such as polyphenols, carotenoids, flavonoids, phytoestrogens, and to a higher activity of antioxidant enzymes. In this review we discuss reports on health-promoting phytochemicals and analytical methods used for their identification and quantification in plants, and on arbuscular mycorrhizal fungi impact on fruits and vegetables nutritional and nutraceutical value., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Over the years, natural products from plants and their non-natural derivatives have shown to be active against different types of chronic diseases. However, isolation of such natural products can be limited due to their low bioavailability, and environmental restrictions. To address these issues, in vivo and in vitro reconstruction of plant metabolic pathways and the metabolic engineering of microbes and plants have been used to generate libraries of compounds. Significant advances have been made through metabolic engineering of microbes and plant cells to generate a variety of compounds (e.g. isoprenoids, flavonoids, or stilbenes) using a diverse array of methods to optimize these processes (e.g. host selection, operational variables, precursor selection, gene modifications). These approaches have been used also to generate non-natural analogues with different bioactivities. In vitro biosynthesis allows the synthesis of intermediates as well as final products avoiding post-translational limitations. Moreover, this strategy allows the use of substrates and the production of metabolites that could be toxic for cells, or expand the biosynthesis into non-conventional media (e.g. organic solvents, supercritical fluids). A perspective is also provided on the challenges for generating novel chemical structures and the potential of combining metabolic engineering and in vitro biocatalysis to produce metabolites with more potent biological activities., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)