Explore the vast range of titles available.

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of the major groups of secondary metabolites found in plants. Researchers from distinct research fields, including pharmacology, medicine, and agriculture, are interested in their biological potential. With new SL discovered in the last years, new biological activities have been tested, different action mechanisms (synergistic and/or antagonistic effects), as well as molecular structure–activity relationships described. The review identifies the main sesquiterpene lactones with interconnections between immune responses and anti-inflammatory actions, within different cellular models as well in in vivo studies. Bioaccessibility and bioavailability, as well as molecular structure–activity relationships are addressed. Additionally, plant metabolic engineering, and the impact of sesquiterpene lactone extraction methodologies are presented, with the perspective of biological activity enhancement. Sesquiterpene lactones derivatives are also addressed. This review summarizes the current knowledge regarding the therapeutic potential of sesquiterpene lactones within immune and inflammatory activities, highlighting trends and opportunities for their pharmaceutical/clinical use.

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years 1 – 7 . However, the field has progressed greatly since the development of early programs such as LHASA 1 , 7 , for which reaction choices at each step were made by human operators. Multiple software platforms 6 , 8 – 14 are now capable of completely autonomous planning. But these programs ‘think’ only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary 15 , 16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program’s knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships 17 , 18 , allowing it to ‘strategize’ over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts.

Structural, biochemical, mass spectrometry and genetic analyses define Arabidopsis thaliana AtD14 as a non-canonical hormone receptor for strigolactone, which hydrolyses strigolactone into a covalently linked intermediate molecule and undergoes an open-to-closed state transition for interaction with D3 to trigger strigolactone signalling. Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The α/β hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection 1 , 2 , 3 . However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14–D3–ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone. Strigolactone receptor doubles as a hydrolase Many years of biological research have contributed to the prevailing view of how a hormone works: the active hormone binds to a receptor to trigger signal transduction and later the unchanged hormone molecule is released. This differentiates hormone–receptor interaction from substrate–enzyme interaction. Now Daoxin Xie and colleagues have obtained the crystal structure of a synthetic analogue of the plant branching hormone strigolactone with its receptor complex (D14–D3–ASK1), revealing an unusual mechanism of ligand–receptor interaction. They find that D14 hydrolyses strigolactone into a covalently linked intermediate molecule. This intermediate allosterically activates the receptor function of D14 by initiating conformational changes that facilitate interaction with D3. The data provide evidence that the receptor function and enzymatic activity of D14 are separable.

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.

Abstract Strigolactones are endogenous plant hormones regulating plant development and are exuded into the rhizosphere when plants experience nutrient deficiency. There, they promote the mutualistic association of plants with arbuscular mycorrhizal fungi that help the plant with the uptake of nutrients from the soil. This shows that plants actively establish—through the exudation of strigolactones—mutualistic interactions with microbes to overcome inadequate nutrition. The signaling function of strigolactones could possibly extend to other microbial partners, but the effect of strigolactones on the global root and rhizosphere microbiome remains poorly understood. Therefore, we analyzed the bacterial and fungal microbial communities of 16 rice genotypes differing in their root strigolactone exudation. Using multivariate analyses, distinctive differences in the microbiome composition were uncovered depending on strigolactone exudation. Moreover, the results of regression modeling showed that structural differences in the exuded strigolactones affected different sets of microbes. In particular, orobanchol was linked to the relative abundance of Burkholderia–Caballeronia–Paraburkholderia and Acidobacteria that potentially solubilize phosphate, while 4-deoxyorobanchol was associated with the genera Dyella and Umbelopsis. With this research, we provide new insight into the role of strigolactones in the interplay between plants and microbes in the rhizosphere. A new perspective on the role of strigolactones as a rhizosphere signaling molecule in the interaction between plants and their rhizosphere and root microbiome.

Shoot branching is a major determinant of plant architecture and is highly regulated by endogenous and environmental cues. Two classes of hormones, auxin and cytokinin, have long been known to have an important involvement in controlling shoot branching. Previous studies using a series of mutants with enhanced shoot branching suggested the existence of a third class of hormone(s) that is derived from carotenoids, but its chemical identity has been unknown. Here we show that levels of strigolactones, a group of terpenoid lactones, are significantly reduced in some of the branching mutants. Furthermore, application of strigolactones inhibits shoot branching in these mutants. Strigolactones were previously found in root exudates acting as communication chemicals with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Thus, we propose that strigolactones act as a new hormone class—or their biosynthetic precursors—in regulating above-ground plant architecture, and also have a function in underground communication with other neighbouring organisms. Branching out: new class of plant hormones inhibits branch formation For many years the textbooks recognized five 'classic' plant hormones: auxin, gibberellins, ethylene, cytokinin and abscisic acid. To these can be added the brassinosteroids, nitric oxide and jasmonates, among others, as phytohormones or plant growth regulators. Shoot branching is regulated by hormones, with both auxin and cytokinin playing a part. But the existence of mutants with enhanced branching in several species suggested a third factor was involved, a novel plant hormone released from the roots that prevents excessive shoot branching. Two groups now identify a class of chemical compounds called strigolactones — or one of their derivatives — as that missing hormone. Strigolactones are found in root exudates and are reduced in the branching mutants; external application of these chemicals inhibits shoot branching in the mutants. Shoot branching is regulated by hormones. Branching mutants in several plant species suggests the existence of a plant hormone that is released from the roots and prevents excessive shoot branching. This paper reports on one of two studies that show that a class of chemical compounds called strigolactones found in root exudates are reduced in the branching mutants and that external application of these chemicals inhibits shoot branching in the mutants. It is proposed that strigolactones or related metabolites are the sought after class of hormones.

The strigolactones, a class of plant hormones, regulate many aspects of plant physiology. In the inhibition of shoot branching, the α/β hydrolase D14—which metabolizes strigolactone—interacts with the F-box protein D3 to ubiquitinate and degrade the transcription repressor D53. Despite the fact that multiple modes of interaction between D14 and strigolactone have recently been determined, how the hydrolase functions with D3 to mediate hormone-dependent D53 ubiquitination remains unknown. Here we show that D3 has a C-terminal α-helix that can switch between two conformational states. The engaged form of this α-helix facilitates the binding of D3 and D14 with a hydrolysed strigolactone intermediate, whereas the dislodged form can recognize unmodified D14 in an open conformation and inhibits its enzymatic activity. The D3 C-terminal α-helix enables D14 to recruit D53 in a strigolactone-dependent manner, which in turn activates the hydrolase. By revealing the structural plasticity of the SCF D3–D14 ubiquitin ligase, our results suggest a mechanism by which the E3 coordinates strigolactone signalling and metabolism. The plant F-box protein D3 has a C-terminal α-helix that switches between two conformational states, allowing the α/β hydrolase D14 to recruit the transcription repressor D53 for strigolactone-dependent degradation.

Striga is a major biotic constraint to sorghum production in semiarid tropical Africa and Asia. Genetic resistance to this parasitic weed is the most economically feasible control measure. Mutant alleles at the LGS1 (LOW GERMINATION STIMULANT 1) locus drastically reduce Striga germination stimulant activity. We provide evidence that the responsible gene at LGS1 codes for an enzyme annotated as a sulfotransferase and show that functional loss of this gene results in a change of the dominant strigolactone (SL) in root exudates from 5-deoxystrigol, a highly active Striga germination stimulant, to orobanchol, an SL with opposite stereochemistry. Orobanchol, although not previously reported in sorghum, functions in the multiple SL roles required for normal growth and environmental responsiveness but does not stimulate germination of Striga. This work describes the identification of a gene regulating Striga resistance and the underlying protective chemistry resulting from mutation.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Summary of the chemistry of canonical and non-canonical strigolactones and their distribution in the plant kingdom in relation to their biological activities in the rhizosphere and in plants. Abstract Strigolactones (SLs) can be classified into two structurally distinct groups: canonical and non-canonical SLs. Canonical SLs contain the ABCD ring system, and non-canonical SLs lack the A, B, or C ring but have the enol ether-D ring moiety, which is essential for biological activities. The simplest non-canonical SL is the SL biosynthetic intermediate carlactone. In plants, carlactone and its oxidized metabolites, such as carlactonoic acid and methyl carlactonoate, are present in root and shoot tissues. In some plant species, including black oat (Avena strigosa), sunflower (Helianthus annuus), and maize (Zea mays), non-canonical SLs in the root exudates are major germination stimulants. Various plant species, such as tomato (Solanum lycopersicum), Arabidopsis, and poplar (Populus spp.), release carlactonoic acid into the rhizosphere. These observations suggest that both canonical and non-canonical SLs act as host-recognition signals in the rhizosphere. In contrast, the limited distribution of canonical SLs in the plant kingdom, and the structure-specific and stereospecific transportation of canonical SLs from roots to shoots, suggest that plant hormones inhibiting shoot branching are not canonical SLs but, rather, are non-canonical SLs.