1. Synthesis and Conformational Analysis of Efrapeptins
- Author
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Karlheinz Altendorf, Norbert Sewald, Miklós Hollósi, Quirinus B. Broxterman, Jörg Christian Greie, Frank Hofmann, Elemér Vass, Bernard Kaptein, Thomas Huber, Horst Kessler, Sven Weigelt, Markus Ritzefeld, Burkhard Luy, Micha Jost, Christoph Freudenberger, Lavinia Panella, and Zsuzsanna Majer
- Subjects
Models, Molecular ,Protein Structure ,Secondary ,Circular dichroism ,Peptides/chemical synthesis ,Molecular model ,Stereochemistry ,Nuclear Magnetic Resonance ,Molecular Sequence Data ,Anti-Bacterial Agents/chemistry ,Anti-Bacterial Agents/chemical synthesis ,Peptide ,Peptides/chemistry ,Protein Structure, Secondary ,Catalysis ,Anti-Bacterial Agents/pharmacology ,chemistry.chemical_compound ,Models ,Escherichia coli ,Amino Acid Sequence ,Escherichia coli/enzymology ,Nuclear Magnetic Resonance, Biomolecular ,Pipecolic acid ,Adenosine Triphosphatases ,Peptides/pharmacology ,chemistry.chemical_classification ,Circular Dichroism ,Hypocreales/chemistry ,Organic Chemistry ,Efrapeptin ,Molecular ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Anti-Bacterial Agents ,Amino acid ,Enzyme ,chemistry ,Hypocreales ,Adenosine Triphosphatases/antagonists & inhibitors ,Peptides ,Biomolecular - Abstract
The efrapeptin family of peptide antibiotics produced by the fungus Tolypocladium niveum, and the neo-efrapeptins from the fungus Geotrichum candidumare inhibitors of F(1)-ATPase with promising antitumor, antimalaria, and insecticidal activity. They are rich in C(α)-dialkyl amino acids (Aib, Iva, Acc) and contain one β-alanine and several pipecolic acid residues. The C-terminus bears an unusual heterocyclic cationic cap. The efrapeptins C-G and three analogues of efrapeptin C were synthesized using α-azido carboxylic acids as masked amino acid derivatives. All compounds display inhibitory activity toward F(1)-ATPase. The conformation in solution of the peptides was investigated with electronic CD spectroscopy, FT-IR spectroscopy, and VCD spectroscopy. All efrapeptins and most efrapeptin analogues were shown to adopt helical conformations in solution. In the case of efrapeptin C, VCD spectra proved that a 3(10)-helix prevails. In addition, efrapeptin C was conformationally studied in detail with NMR and molecular modeling. Besides NOE distance restraints, residual dipolar couplings (RDC) observed upon partial alignment with stretched PDMS gels were used for the conformational analysis and confirmed the 3(10)-helical conformation.
- Published
- 2011
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