Toni Kühl

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (8)32.37 Total impact

  • Toni Kühl, Diana Imhof
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    ABSTRACT: More than 20 years of research on heme as a temporary effector molecule of proteins have revealed its widespread impact on virtually all primary functions in the human organism. As our understanding of this influence is still growing, a comprehensive overview of compiled data will give fresh impetus for creativity and developing new strategies in heme-related research. From known data concerning heme-regulated proteins and their involvement in the development of diseases, we provide concise information of FeII/III heme as a regulator and the availability of “regulatory heme”. The latter is dependent on the balance between free and bound FeII/III heme, here termed “hemeostasis”. Imbalance of this system can lead to the development of diseases that were not always attributed to this small molecule. Diseases such as cancer or Alzheimer's disease highlight the reawakened interest in heme, whose function was previously believed to be completely understood.
    ChemBioChem 09/2014; · 3.74 Impact Factor
  • Tetrahedron Letters 01/2014; 55(27):3658–3662. · 2.40 Impact Factor
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    ABSTRACT: Regulatory heme binds to specific motifs in proteins and controls a variety of biochemical processes. Several of these proteins were recently shown to form complexes with ferric and/or ferrous heme via a cysteine residue as axial ligand. The objective of this study was to examine the heme-binding properties of a series of cysteine-containing peptides with focus on CP motif sequences. The peptides displayed different binding behavior upon Fe(III) heme application with characteristic wavelength shifts of the Soret band to 370 nm or 420-430 nm, and in some cases to both wavelengths. While for most of the peptides containing a cysteine only a shift to 420-430 nm was observed, CP-containing peptides exhibited a preference for a shift to 370 nm. Detailed structural investigation using Raman and NMR spectroscopy on selected representatives revealed different binding modes with respect to iron ion coordination, which reflected the results of the UV-vis studies. A predicted short sequence stretch derived from dipeptidyl peptidase 8 was additionally examined with respect to CP motif binding to heme on the peptide as well as on the protein level. The heme association was confirmed with the first solution structure of a CP-peptide-heme complex and, moreover, an inhibitory effect of Fe(III) heme on the enzyme's activity. The relevance of both, the use of model compounds to elucidate the molecular mechanism underlying regulatory heme binding and its potential for the investigation of regulatory heme control, is discussed.
    ACS Chemical Biology 06/2013; · 5.44 Impact Factor
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    ABSTRACT: The one and only fold? Three chemically synthesized μ-conotoxin PIIIA isomers, which contain different disulfide connectivity, block the skeletal muscle voltage-gated sodium channel Na(V) 1.4 with similar, yet distinguishable potency. Hence, bioactivity of this μ-conotoxin is not strictly coupled to its native fold. Future development of conotoxin-derived analgesics may benefit from such a widened structural repertoire.
    Angewandte Chemie International Edition 03/2012; 51(17):4058-4061. · 11.34 Impact Factor
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    ABSTRACT: Die einzig wahre Faltung? Drei chemisch synthetisierte Isomere von μ‐Conotoxin PIIIA mit unterschiedlicher Disulfidkonnektivität blockieren den spannungsgesteuerten Natriumkanal NaV1.4 mit ähnlichen, wenn auch unterscheidbaren Wirkungen. Damit ist nachgewiesen, dass auch nicht‐nativ gefaltete μ‐Conotoxine biologische Aktivität aufweisen. Zukünftige Entwicklungen Conotoxin‐abgeleiteter Analgetika könnten von solch einem erweiterten Strukturrepertoire profitieren.
    Angewandte Chemie 03/2012; 124(17):4134-4137.
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    ABSTRACT: Tridegin, a 66-mer peptide isolated from the leech Haementeria ghilianii, is a potent inhibitor of the coagulation factor XIIIa. This paper describes the chemical synthesis of tridegin by two different strategies--solid-phase assembly and native chemical ligation--both followed by oxidation in solution phase. Tridegin and truncated analogues were examined for their activity and revealed a particular importance of the C-terminal region of the parent peptide. Based on these studies a minimal sequence required for factor XIIIa inhibition could be identified. Our data revealed that the glutamine residue at position 52 (Q52) of tridegin most likely binds to the active site of factor XIIIa and was therefore suggested to react with the enzyme. The function of the N-terminal region is also discussed, as the isolated C-terminal segment of tridegin lost its inhibitory activity rapidly in the presence of factor XIIIa, whereas this was not the case for the full-length inhibitor.
    ChemMedChem 12/2011; 7(2):326-33. · 2.84 Impact Factor
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    ABSTRACT: Studies of the binding of heme/hemin to proteins or peptides have recently intensified as it became evident that heme serves not only as a prosthetic group, but also as a regulator and effector molecule interacting with transmembrane and cytoplasmic proteins. The iron-ion-containing heme group can associate with these proteins in different ways, with the amino acids Cys, His, and Tyr allowing individual modes of binding. Strong coordinate-covalent binding, such as in cytochrome c, is known, and reversible attachment is also discussed. Ligands for both types of binding have been reported independently, though sometimes with different affinities for similar sequences. We applied a combinatorial approach using the library (X)(4) (C/H/Y)(X)(4) to characterize peptide ligands with considerable hemin binding capacities. Some of the library-selected peptides were comparable in terms of hemin association independently of whether or not a cysteine residue was present in the sequence. Indeed, a preference for His-based (≈39 %) and Tyr-based (≈40 %) sequences over Cys-based ones (≈21 %) was detected. The binding affinities for the library-selected peptides, as determined by UV/Vis spectroscopy, were in the nanomolar range. Moreover, selected representatives efficiently competed for hemin binding with the human BK channel hSlo1, which is known to be regulated by heme through binding to its heme-binding domain.
    ChemBioChem 11/2011; 12(18):2846-55. · 3.74 Impact Factor
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    ABSTRACT: A sequence derived from the epithelial receptor tyrosine kinase Ros (pY2267) represents a high-affinity binding partner for protein tyrosine phosphatase SHP-1 and was recently used as lead structure to analyze the recognition requirements for the enzyme's N-SH2 domain. Here, we focused on a set of peptides comprising C-terminally extended linear and conformationally constrained side chain-bridged cyclic N-SH2 ligands based on the consensus sequence LxpYhxh(h/b)(h/b) (x = any amino acid, h = hydrophobic, and b = basic residue). Furthermore, the bivalent peptides described were designed to modulate the activity of SHP-1 through binding to both, the N-SH2 domain as well as an independent binding site on the surface of the catalytic domain (PTP domain). Consistent with previous experimental findings, surface plasmon resonance experiments revealed dissociation constants of most compounds in the low micromolar range. One peptide, EGLNpYc[KVD]MFPAPEEE--NH(2), displayed favorable binding affinity, but reduced ability to stimulate SHP-1. Docking experiments revealed that the binding of this ligand occurs in binding mode I, recently described to lead to an inhibited activation of SHP-1. In summary, results presented in this study suggest that inhibitory N-SH2 ligands of SHP-1 may be obtained by designing bivalent compounds that associate with the N-SH2 domain and simultaneously occupy a specific binding site on the PTP domain.
    Biopolymers 09/2009; 93(1):102-12. · 2.88 Impact Factor

Publication Stats

14 Citations
32.37 Total Impact Points

Institutions

  • 2011–2014
    • University of Bonn
      • Pharmaceutical Institute
      Bonn, North Rhine-Westphalia, Germany
  • 2009–2011
    • Friedrich-Schiller-University Jena
      • • Institut für Biochemie und Biophysik
      • • Center of Molecular Biomedicine
      Jena, Thuringia, Germany