Omanische Heilpflanze im Fokus der Phytochemie IPB-Wissenschaftler und Partner aus Dhofar haben jüngst die omanische Heilpflanze Terminalia dhofarica unter die phytochemische Lupe genommen. Die Pflanze ist reich an…
Geschmack ist vorhersagbar: Mit FlavorMiner. FlavorMiner heißt das Tool, das IPB-Chemiker und Partner aus Kolumbien jüngst entwickelt haben. Das Programm kann, basierend auf maschinellem Lernen (KI), anhand der…
Plant phytohormone pathways are regulated by an intricate network of signaling components and modulators, many of which still remain unknown. Here, we report a forward chemical genetics approach for the identification of functional SA agonists in Arabidopsis thaliana that revealed Neratinib (Ner), a covalent pan-HER kinase inhibitor drug in humans, as a modulator of SA signaling. Instead of a protein kinase, chemoproteomics unveiled that Ner covalently modifies a surface-exposed cysteine residue of Arabidopsis epoxide hydrolase isoform 7 (AtEH7), thereby triggering its allosteric inhibition. Physiologically, the Ner application induces jasmonate metabolism in an AtEH7-dependent manner as an early response. In addition, it modulates PATHOGENESIS RELATED 1 (PR1) expression as a hallmark of SA signaling activation as a later effect. AtEH7, however, is not the exclusive target for this physiological readout induced by Ner. Although the underlying molecular mechanisms of AtEH7-dependent modulation of jasmonate signaling and Ner-induced PR1-dependent activation of SA signaling and thus defense response regulation remain unknown, our present work illustrates the powerful combination of forward chemical genetics and chemical proteomics for identifying novel phytohormone signaling modulatory factors. It also suggests that marginally explored metabolic enzymes such as epoxide hydrolases may have further physiological roles in modulating signaling.
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Rajakumara, E.; Abhishek, S.; Nitin, K.; Saniya, D.; Bajaj, P.; Schwaneberg, U.; Davari, M. D.;Structure and cooperativity in substrate–enzyme interactions: Perspectives on enzyme engineering and inhibitor designACS Chem. Biol.17266-280(2022)DOI: 10.1021/acschembio.1c00500
Enzyme-based synthetic chemistry provides a green way to synthesize industrially important chemical scaffolds and provides incomparable substrate specificity and unmatched stereo-, regio-, and chemoselective product formation. However, using biocatalysts at an industrial scale has its challenges, like their narrow substrate scope, limited stability in large-scale one-pot reactions, and low expression levels. These limitations can be overcome by engineering and fine-tuning these biocatalysts using advanced protein engineering methods. A detailed understanding of the enzyme structure and catalytic mechanism and its structure–function relationship, cooperativity in binding of substrates, and dynamics of substrate–enzyme–cofactor complexes is essential for rational enzyme engineering for a specific purpose. This Review covers all these aspects along with an in-depth categorization of various industrially and pharmaceutically crucial bisubstrate enzymes based on their reaction mechanisms and their active site and substrate/cofactor-binding site structures. As the bisubstrate enzymes constitute around 60% of the known industrially important enzymes, studying their mechanism of actions and structure–activity relationship gives significant insight into deciding the targets for protein engineering for developing industrial biocatalysts. Thus, this Review is focused on providing a comprehensive knowledge of the bisubstrate enzymes’ structure, their mechanisms, and protein engineering approaches to develop them into industrial biocatalysts.
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Holzmeyer, L.; Hartig, A.-K.; Franke, K.; Brandt, W.; Muellner-Riehl, A. N.; Wessjohann, L. A.; Schnitzler, J.;Evaluation of plant sources for antiinfective lead compound discovery by correlating phylogenetic, spatial, and bioactivity dataProc. Natl. Acad. Sci. U.S.A.11712444-12451(2020)DOI: 10.1073/pnas.1915277117
The continued high rates of using antibiotics in healthcare and livestock, without sufficient new compounds reaching the market, has led to a dramatic increase in antimicrobial resistance, with multidrug-resistant bacteria emerging as a major public health threat worldwide. Because the vast majority of antiinfectives are natural products or have originated from them, we assessed the predictive power of plant molecular phylogenies and species distribution modeling in the search for clades and areas which promise to provide a higher probability of delivering new antiinfective compound leads. Our approach enables taxonomically and spatially targeted bioprospecting and supports the battle against the global antimicrobial crisis.
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Serra, P.; Carbonell, A.; Navarro, B.; Gago-Zachert, S.; Li, S.; Di Serio, F.; Flores, R.;Symptomatic plant viroid infections in phytopathogenic fungi: A request for a critical reassessmentProc. Natl. Acad. Sci. U.S.A.11710126-10128(2020)DOI: 10.1073/pnas.1922249117