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…
Seit Februar 2021 bietet Wolfgang Brandt, ehemaliger Leiter der Arbeitsgruppe Computerchemie am IPB, sein Citizen Science-Projekt zur Pilzbestimmung an. Dafür hat er in regelmäßigen Abständen öffentliche Vorträge zur Vielfalt…
Ricardo, M. G.; Llanes, D.; Rennert, R.; Jänicke, P.; Rivera, D. G.; Wessjohann, L. A.;Improved access to potent anticancer tubulysins and linker‐functionalized payloads via an all‐on‐resin strategyChem.-Eur. J.30e202401943(2024)DOI: 10.1002/chem.202401943
Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide‐drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e.g., by using small tertiary amide N‐substituents (Me, Et, Pr) on tubuvaline residue. Cumbersome solution‐phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p‐Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all‐on‐resin strategy permitting a loss‐free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on‐resin tubulysin derivatization with, e.g., a maleimido‐Val‐Cit‐PABQ linker, which is a notable progress for the payload‐PABQ‐linker technology. The strategy also allows tubulysin diversification of the internal amide N‐substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker‐attachment and functionalization.
Publikation
Picchianti, L.; Sanchez de Medina Hernandez, V.; Zhan, N.; Irwin, N. A.; Groh, R.; Stephani, M.; Hornegger, H.; Beveridge, R.; Sawa‐Makarska, J.; Lendl, T.; Grujic, N.; Naumann, C.; Martens, S.; Richards, T. A.; Clausen, T.; Ramundo, S.; Karagöz, G. E.; Dagdas, Y.;Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagyEMBO J.42e112053(2023)DOI: 10.15252/embj.2022112053
UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin-fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER-bound ribosomes and activates C53-mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8-interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM-mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation-dependent fine-tuning of C53-mediated autophagy activation.
Publikation
Ai, H.; Bellstaedt, J.; Bartusch, K. S.; Eschen‐Lippold, L.; Babben, S.; Balcke, G. U.; Tissier, A.; Hause, B.; Andersen, T. G.; Delker, C.; Quint, M.;Auxin‐dependent regulation of cell division rates governs root thermomorphogenesisEMBO J.42e111926(2023)DOI: 10.15252/embj.2022111926
Roots are highly plastic organs enabling plants to adapt to a changing below-ground environment. In addition to abiotic factors like nutrients or mechanical resistance, plant roots also respond to temperature variation. Below the heat stress threshold, Arabidopsis thaliana seedlings react to elevated temperature by promoting primary root growth, possibly to reach deeper soil regions with potentially better water saturation. While above-ground thermomorphogenesis is enabled by thermo-sensitive cell elongation, it was unknown how temperature modulates root growth. We here show that roots are able to sense and respond to elevated temperature independently of shoot-derived signals. This response is mediated by a yet unknown root thermosensor that employs auxin as a messenger to relay temperature signals to the cell cycle. Growth promotion is achieved primarily by increasing cell division rates in the root apical meristem, depending on de novo local auxin biosynthesis and temperature-sensitive organization of the polar auxin transport system. Hence, the primary cellular target of elevated ambient temperature differs fundamentally between root and shoot tissues, while the messenger auxin remains the same.
Publikation
Ricardo, M. G.; Schwark, M.; Llanes, D.; Niedermeyer, T. H. J.; Westermann, B.;Total synthesis of Aetokthonotoxin, the cyanobacterial neurotoxin causing vacuolar myelinopathyChem.-Eur. J.2712032-12035(2021)DOI: 10.1002/chem.202101848
Aetokthonotoxin has recently been identified as the cyanobacterial neurotoxin causing Vacuolar Myelinopathy, a fatal neurologic disease, spreading through a trophic cascade and affecting birds of prey such as the bald eagle in the USA. Here, we describe the total synthesis of this specialized metabolite. The complex, highly brominated 1,2’-biindole could be synthesized via a Somei-type Michael reaction as key step. The optimised sequence yielded the natural product in five steps with an overall yield of 29 %.