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…
Müllers, Y.; Sadr, A. S.; Schenderlein, M.; Pallab, N.; D. Davari, M.; Glebe, U.; Reifarth, M.;Acrylate‐derived RAFT polymers for enzyme hyperactivation – boosting the α‐chymotrypsin enzyme activity using tailor‐made poly(2‐carboxyethyl)acrylate (PCEA)ChemCatChem16e202301685(2024)DOI: 10.1002/cctc.202301685
We study the hyperactivation of α‐chymotrypsin (α‐ChT) using the acrylate polymer poly(2‐carboxyethyl) acrylate (PCEA) in comparison to the commonly used poly(acrylic acid) (PAA). The polymers are added during the enzymatic cleavage reaction of the substrate N‐glutaryl‐L‐phenylalanine p‐nitroanilide (GPNA). Enzyme activity assays reveal a pronounced enzyme hyperactivation capacity of PCEA, which reaches up to 950% activity enhancement, and is significantly superior to PAA (revealing an activity enhancement of approx. 450%). In a combined experimental and computational study, we investigate α‐ChT/polymer interactions to elucidate the hyperactivation mechanism of the enzyme. Isothermal titration calorimetry reveals a pronounced complexation between the polymer and the enzyme. Docking simulations reveal that binding of polymers significantly improves the binding affinity of GPNA to α‐ChT. Notably, a higher binding affinity is found for the α‐ChT/PCEA compared to the α‐ChT/PAA complex. Further molecular dynamics (MD) simulations reveal changes in the size of the active site in the enzyme/polymer complexes, with PCEA inducing a more pronounced alteration compared to PAA, facilitating an easier access for the substrate to the active site of α‐ChT.
Publikation
Dippe, M.; Davari, M. D.; Weigel, B.; Heinke, R.; Vogt, T.; Wessjohann, L. A.;Altering the regiospecificity of a catechol
O‐methyltransferase through rational design: Vanilloid vs. isovanilloid motifs in the B‐ring of flavonoidsChemCatChem14e202200511(2022)DOI: 10.1002/cctc.202200511
Rational re-design of the substrate pocket of phenylpropanoid-flavonoid O-methyltransferase (PFOMT) from Mesembryanthe-mum crystallinum, an enzyme that selectively methylates the 3’-position (= meta-position) in catechol-moieties of flavonoids to guiacol-moieties, provided the basis for the generation of variants with opposite, i. e. 4’- (para-) regioselectivity and enhanced catalytic efficiency. A double variant (Y51R/N202W) identified through a newly developed colorimetric assay efficiently modified the para-position in flavanone and flavano-nol substrates, providing access to the sweetener molecule hesperetin and other rare plant flavonoids having an isovanil-loid motif.
Publikation
Vasco, A. V.; Ceballos, L. G.; Wessjohann, L. A.; Rivera, D. G.;Multicomponent functionalization of the octreotide peptide macrocyclic scaffoldEur. J. Org. Chem.2022e202200687(2022)DOI: 10.1002/ejoc.202200687
The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an onresin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.
Publikation
Ditfe, T.; Bette, E.; N. Sultani, H.; Otto, A.; Wessjohann, L. A.; Arnold, N.; Westermann, B.;Synthesis and biological evaluation of highly potent fungicidal deoxy‐hygrophoronesEur. J. Org. Chem.20213827-3836(2021)DOI: 10.1002/ejoc.202100729
Although stripped from hydroxyl-groups, deoxygenated
hygrophorones remain highly active against severe phytopathogens. The
synthesis to these natural product congeners is achieved in
rearrangement sequences, with an optimized deprotection strategy
avoiding retro-aldol reactions. The activities are comparable to
fungicides used in agriculture.
Based on naturally occurring hygrophorones, racemic di-
and mono-hydroxylated cyclopentenones bearing an aliphatic side chain
have been produced in short synthetic sequences starting from furfuryl
aldehyde. For the series of dihydroxylated trans-configured derivatives, an Achmatowicz-rearrangement and a Caddick-ring contraction were employed, and for the series of trans-configured
mono-hydroxylated derivatives a Piancatelli-rearrangement. All final
products showed good to excellent fungicidal activities against the
plant pathogens B. cinerea, S. tritici and P. infestans.