Phytosiderophore pathway response in barley exposed to iron, zinc or copper starvation.

Efficient micronutrient acquisition is a critical factor in selecting micronutrient dense crops for human consumption. Enhanced exudation and re-uptake of metal chelators, so-called phytosiderophores, by roots of graminaceous plants has been implicated in efficient micronutrient acquisition. We compared PS biosynthesis and exudation as a response mechanism to either Fe, Zn or Cu starvation. Two barley (Hordeum vulgare L.) lines with contrasting micronutrient grain yields were grown hydroponically and PS exudation (LC-MS) and root gene expression (RNAseq) were determined after either Fe, Zn, or Cu starvation. The response strength of the PS pathway was micronutrient dependent and decreased in the order Fe > Zn > Cu deficiency. We observed a stronger expression of PS pathway genes and greater PS exudation in the barley line with large micronutrient grain yield suggesting that a highly expressed PS pathway might be an important trait involved in high micronutrient accumulation. In addition to several metal specific transporters, we also found that the expression of IRO2 and bHLH156 transcription factors was not only induced under Fe but also under Zn and Cu deficiency. Our study delivers important insights into the role of the PS pathway in the acquisition of different micronutrients.

Burkholderia cenocepacia lectin A binding to heptoses from the bacterial lipopolysaccharide.

Bacteria from the Burkholderia cepacia complex (Bcc) cause highly contagious pneumonia among cystic fibrosis (CF) patients. Among them, Burkholderia cenocepacia is one of the most dangerous in the Bcc and is the most frequent cause of morbidity and mortality in CF patients. Indeed, it is responsible of "cepacia syndrome", a deadly exacerbation of infection, that is the main cause of poor outcomes in lung transplantation. Burkholderia cenocepacia produces several soluble lectins with specificity for fucosylated and mannosylated glycoconjugates. These lectins are present on the bacterial cell surface and it has been proposed that they bind to lipopolysaccharide epitopes. In this work, we report on the interaction of one B. cenocepacia lectin, BC2L-A, with heptose and other manno configured sugar residues. Saturation transfer difference NMR spectroscopy studies of BC2L-A with different mono- and disaccharides demonstrated the requirement of manno configuration with the hydroxyl or glycol group at C6 for the binding process. The crystal structure of BC2L-A complexed with the methyl-heptoside confirmed the location of the carbohydrate ring in the binding site and elucidated the orientation of the glycol tail, in agreement with NMR data. Titration calorimetry performed on monosaccharides, heptose disaccharides and bacterial heptose-containing oligosaccharides and polysaccharides confirmed that bacterial cell wall contains carbohydrate epitopes that can bind to BC2L-A. Additionally, the specific binding of fluorescent BC2L-A lectin on B. cenocepacia bacterial surface was demonstrated by microscopy.

Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11ß-hydroxysteroid dehydrogenase 2 inhibitors.

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 and type 2. Whereas inhibition of 11ß-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11ß-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11ß-HSD2. The most potent and selective compound is active against human 11ß-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11ß-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11ß-HSD1 and 11ß-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11ß-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.

Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11ß-hydroxysteroid dehydrogenase 2 inhibitors.

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 and type 2. Whereas inhibition of 11ß-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11ß-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11ß-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11ß-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11ß-HSD1 and 11ß-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11ß-HSD2. The most potent and selective compound is active against human 11ß-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11ß-HSD1.