Recent developments in synthetic biology, combined with continued progress in systems biology and metabolic engineering, have enabled the engineering of microorganisms to produce heterologous molecules in a manner that was previously unfeasible. The successful synthesis and recent entry of semi-synthetic artemisinin into commercial production is the first demonstration of the potential of synthetic biology for the development and production of pharmaceutical agents. In this Review, we describe the metabolic engineering and synthetic biology approaches that were used to develop this important antimalarial drug precursor. This not only demonstrates the incredible potential of the available technologies but also illuminates how lessons learned from this work could be applied to the production of other pharmaceutical agents.

Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development

Lipids are distributed in a highly heterogeneous fashion in different cellular membranes. Only a minority of lipids achieve their final intracellular distribution through transport by vesicles. Instead, the bulk of lipid traffic is mediated by a large group of lipid transfer proteins (LTPs), which move small numbers of lipids at a time using hydrophobic cavities that stabilize lipid molecules outside membranes. Although the first LTPs were discovered almost 50 years ago, most progress in understanding these proteins has been made in the past few years, leading to considerable temporal and spatial refinement of our understanding of the function of these lipid transporters. The number of known LTPs has increased, with exciting discoveries of their multimeric assembly. Structural studies of LTPs have progressed from static crystal structures to dynamic structural approaches that show how conformational changes contribute to lipid handling at a sub-millisecond timescale. A major development has been the finding that many intracellular LTPs localize to two organelles at the same time, forming a shuttle, bridge or tube that links donor and acceptor compartments. The understanding of how different lipids achieve their final destination at the molecular level allows a better explanation of the range of defects that occur in diseases associated with lipid transport and distribution, opening up the possibility of developing therapies that specifically target lipid transfer.

/pdf/lipid-transfer-proteins-the-lipid-commute-via-shuttles-36rsn01986.pdf

Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes.

Strigolactones (SLs) are a class of phytohormones and rhizosphere signaling compounds with high structural diversity. Three enzymes, carotenoid isomerase DWARF27 and carotenoid cleavage dioxygenases CCD7 and CCD8, were previously shown to convert all-trans-β-carotene to carlactone (CL), the SL precursor. However, how CL is metabolized to SLs has remained elusive. Here, by reconstituting the SL biosynthetic pathway in Nicotiana benthamiana, we show that a rice homolog of Arabidopsis More Axillary Growth 1 (MAX1), encodes a cytochrome P450 CYP711 subfamily member that acts as a CL oxidase to stereoselectively convert CL into ent-2'-epi-5-deoxystrigol (B-C lactone ring formation), the presumed precursor of rice SLs. A protein encoded by a second rice MAX1 homolog then catalyzes the conversion of ent-2'-epi-5-deoxystrigol to orobanchol. We therefore report that two members of CYP711 enzymes can catalyze two distinct steps in SL biosynthesis, identifying the first enzymes involved in B-C ring closure and a subsequent structural diversification step of SLs.

Rice cytochrome P450 MAX1 homologs catalyze distinct steps in strigolactone biosynthesis

Plants are sessile organisms and, in order to defend themselves against exogenous (a)biotic constraints, they synthesize an array of secondary metabolites which have important physiological and ecological effects. Plant secondary metabolites can be classified into four major classes: terpenoids, phenolic compounds, alkaloids and sulphur-containing compounds. These phytochemicals can be antimicrobial, act as attractants/repellents, or as deterrents against herbivores. The synthesis of such a rich variety of phytochemicals is also observed in undifferentiated plant cells under laboratory conditions and can be further induced with elicitors or by feeding precursors. In this review, we discuss the recent literature on the production of representatives of three plant secondary metabolite classes: artemisinin (a sesquiterpene), lignans (phenolic compounds) and caffeine (an alkaloid). Their respective production in well-known plants, i.e., Artemisia, Coffea arabica L., as well as neglected species, like the fibre-producing plant Urtica dioica L., will be surveyed. The production of artemisinin and caffeine in heterologous hosts will also be discussed. Additionally, metabolic engineering strategies to increase the bioactivity and stability of plant secondary metabolites will be surveyed, by focusing on glycosyltransferases (GTs). We end our review by proposing strategies to enhance the production of plant secondary metabolites in cell cultures by inducing cell wall modifications with chemicals/drugs, or with altered concentrations of the micronutrient boron and the quasi-essential element silicon.

https://www.mdpi.com/2073-4425/9/6/309/pdf/1

Production of Plant Secondary Metabolites: Examples, Tips and Suggestions for Biotechnologists.

Volatiles mediate the interaction of plants with pollinators, herbivores and their natural enemies, other plants and micro-organisms. With increasing knowledge about these interactions the underlying mechanisms turn out to be increasingly complex. The mechanisms of biosynthesis and perception of volatiles are slowly being uncovered. The increasing scientific knowledge can be used to design and apply volatile-based agricultural strategies.

/pdf/the-role-of-volatiles-in-plant-communication-24i165309i.pdf

The role of volatiles in plant communication

Transient production of artemisinin in Nicotiana benthamiana is boosted by a specific lipid transfer protein from A. annua.

Artemisia annua, which produces the anti-malaria compound artemisinin, occurs as high-artemisinin production (HAP) and low-artemisinin production (LAP) chemotypes Understanding the basis of the difference between these chemotypes would assist breeding and optimising artemisinin biosynthesis Here we present a systematic comparison of artemisinin biosynthesis genes that may be involved in determining the chemotype (CYP71AV1, DBR2 and ALDH1) These genes were isolated from the two chemotypes and characterized using transient expression in planta The enzyme activity of DBR2 and ALDH1 from the two chemotypes did not differ, but structural differences in CYP71AV1 from LAP and HAP chemotypes (AMOLAP and AMOHAP, respectively) resulted in altered enzyme activity AMOLAP displays a seven amino acids N-terminal extension compared with AMOHAP The GFP fusion of both proteins show equal localization to the ER but AMOHAP may have reduced stability Upon transient expression in Nicotiana benthamiana, AMOLAP displayed a higher enzyme activity than AMOHAP However, expression in combination with the other pathway genes also resulted in a qualitatively different product profile ('chemotype'); that is, in a shift in the ratio between the unsaturated and saturated (dihydro) branch of the pathway

https://nph.onlinelibrary.wiley.com/doi/pdf/10.1111/nph.12274

The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage

Tetragenococcus halophilus strains are the halophilic lactic acid bacteria (LAB) that are present in microbial communities during soy sauce or other hyperosmotic foods’ fermentation. This species contributes to the formation of volatiles in fermented foods but may experience harsh conditions such as oxidative stress and osmotic stress during fermentation. The characterization of the oxygen tolerance of T. halophilus and elaboration of its antioxidant mechanism are important for the selection of suitable LAB for food fermentation. In this work, the growth of T. halophilus strains isolated from soy sauce moromi under both aerobic and anaerobic conditions was compared, and the function of their antioxidant enzymes was investigated. These strains showed differences in oxidation resistance, and they all produce antioxidant enzymes including superoxide dismutase, peroxidase and glutathione reductase. Interestingly, genes encoding catalase (CAT) are present in the genome of T. halophilus strains, though some of them are pseudogenes. Catalase produced by T. halophilus belongs to the heme-dependent CAT, and its activity could only be detected in the presence of heme under aerobic condition. The CAT from T. halophilus conditionally contributes to resistance to hydrogen peroxide and oxidative stress. These results elucidated the possible antioxidant mechanism of T. halophilus and revealed the differences in the oxidative stress tolerance of T. halophilus strains.

/pdf/heme-dependent-catalase-conditionally-contributes-to-oxygen-1bzs10jt.pdf

Heme Dependent Catalase Conditionally Contributes to Oxygen Tolerance of Tetragenococcus halophilus Strains Isolated from Soy Sauce Moromi

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Transient production of artemisinin in Nicotiana benthamiana is boosted by a specific lipid transfer protein from A. annua.

The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage

Heme Dependent Catalase Conditionally Contributes to Oxygen Tolerance of Tetragenococcus halophilus Strains Isolated from Soy Sauce Moromi