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Publikationen - Natur- und Wirkstoffchemie

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Bücher und Buchkapitel

Baseggio Conrado, A.; Capuozzo, E.; Mosca, L.; Francioso, A.; Fontana, M.; Thiotaurine: From Chemical and Biological Properties to Role in H2S Signaling (Hu, J., et al., eds.). Adv. Exp. Med. Biol. 1155, 755-771, (2019) ISBN: 978-981-13-8023-5 DOI: 10.1007/978-981-13-8023-5_66

In the last decade thiotaurine, 2-aminoethane thiosulfonate, has been investigated as an inflammatory modulating agent as a result of its ability to release hydrogen sulfide (H2S) known to play regulatory roles in inflammation. Thiotaurine can be included in the “taurine family” due to structural similarity to taurine and hypotaurine, and is characterized by the presence of a sulfane sulfur moiety. Thiotaurine can be produced by different pathways, such as the spontaneous transsulfuration between thiocysteine – a persulfide analogue of cysteine – and hypotaurine as well as in vivo from cystine. Moreover, the enzymatic oxidation of cysteamine to hypotaurine and thiotaurine in the presence of inorganic sulfur can occur in animal tissues and last but not least thiotaurine can be generated by the transfer of sulfur from mercaptopyruvate to hypotaurine catalyzed by a sulfurtransferase. Thiotaurine is an effective antioxidant agent as demonstrated by its ability to counteract the damage caused by pro-oxidants in the rat. Recently, we observed the influence of thiotaurine on human neutrophils functional responses. In particular, thiotaurine has been found to prevent human neutrophil spontaneous apoptosis suggesting an alternative or additional role to its antioxidant activity. It is likely that the sulfane sulfur of thiotaurine may modulate neutrophil activation via persulfidation of target proteins. In conclusion, thiotaurine can represent a biologically relevant sulfur donor acting as a biological intermediate in the transport, storage and release of sulfide.
Bücher und Buchkapitel

Wessjohann, L. A.; Ostrowski, S.; Bakulev, V.; Berseneva, V.; Bogdanov, A. V.; Romanova, I. P.; Mironov, V. F.; Larionova, O. A.; Shaikhutdinova, G. R.; Sinyashin, O. G.; Baibulatova, N. Z.; Dokichev, V. A.; Fedorova, O. V.; Ovchinnikova, I. G.; Rusinov, G. L.; Titova, J. A.; Nasonova, A.; Kim, D.-J.; Kim, K.-S.; Jang, Y. M.; Kim, S. J.; Rakhimova, E. B.; Minnebaev, A. B.; Akhmetova, V. R.; Qin, C.; Zhang, R.; Wang, Q.; Ren, J.; Tian, L.; Mironov, M. A.; Demina, T. S.; Tcoy, A. M.; Akopova, T. A.; Markvicheva, E. A.; Chernyshenko, A. O.; Zelenetski, A. N.; Pandit, S. S.; Multi-Component Reactions in Supramolecular Chemistry and Material Science (Mironov, M. A., ed.). Adv. Exp. Med. Biol. 699, 173-201, (2011) ISBN: 978-1-4419-7270-5 DOI: 10.1007/978-1-4419-7270-5_6

Multi-component reactions of building blocks with more than one MCR-reactive group will give rise to oligomeric MCR products. The proper choice of at least two bifunctional building blocks will give either a polymeric or a cyclic product. Apart from polymerization, repetitive or consecutive Ugi reactions have been used to produce linear MCR-heterooligomers with such building blocks.
Bücher und Buchkapitel

Mrestani-Klaus, C.; Brandt, W.; Faust, J.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; New Results on the Conformations of Potent DP IV (CD26) Inhibitors bearing the N-terminal MWP Structural Motif Adv. Exp. Med. Biol. 524, 65-68, (2004) DOI: 10.1007/0-306-47920-6_7

Conformational analysis by NMR spectroscopy and molecular modeling revealed a left-handed PPII helix-like structure for Trp2-Tat(1–9) (cis and trans) and an even more flexible structure for TXA2-R(1–9).PPII helices form a well-defined structural class comparable with the other structures defined in proteins and are characterized by exposed, mobile structures with 4–8 residues, mostly found on the protein surface. Polyproline II helices are mainly identified by their torsion angles of φ∼−75° and Ψ∼145−. They do not form regular interchain hydrogen bonds, but are hydrogen bonded with water molecules. PPII helices have a strong preference for the amino acid proline, although it is not necessarily present. These features were also reported for the parent peptide Tat(1–9)4 as well as for the well known DP IV substrates neuropeptide Y and pancreatic polypeptide5 suggesting that PPII-like helical structures represent a favored structural class for the interaction with DP IV.Thus, the considerable enhancement of the inhibition capacity of both Trp2-Tat(1–9) and TXA2-R(1–9) compared to the moderate inhibitor Tat(1–9)2, Ki=2.68±0.01 10−4 M, can only be due to tryptophan in the second position suggesting that its side chain is favored to exhibit attractive hydrophobic interactions with DP IV compared with aspartic acid.On the other hand, we could show recently that Tat(1–9) and its analogues as well as TXA2-R(1–9) inhibit DP IV according to different inhibition mechanisms (Lorey et al., manuscript submitted). One possible explanation for these findings might be enzyme-ligand interactions relying on multiple weak binding sites as described for PPII helices5 rather than specific lock and key binding. Certainly, only an X-ray structure of DP IV would help to understand the interaction of DP IV with inhibitors.
Bücher und Buchkapitel

Kühn-Wache, K.; Hoffmann, T.; Manhart, S.; Brandt, W.; Demuth, H.-U.; The Specificity of DP IV for Natural Substrates is Peptide Structure Determined Adv. Exp. Med. Biol. 524, 57-63, (2004) DOI: 10.1007/0-306-47920-6_6

Our results indicate that the substrate properties of peptides are encoded by their own structure. That means, that substrate characteristics depend not only on the primary structure around the catalytic site rather C-terminal located secondary interactions strongly influence the binding and catalysis of the substrates. Such interaction sites seem to force the ligand in a proper orientation to the active site of DP IV. As result of these relations the hydrolysis of peptides with non-proline and non-alanine residues in P1-position (Ser, Val, Gly) becomes possible in longer peptides.Such specific secondary interactions opens the opportunity for development of new inhibitors.
Bücher und Buchkapitel

Wrenger, S.; Reinhold, D.; Faust, J.; Mrestani-Klaus, C.; Brandt, W.; Fengler, A.; Neubert, K.; Ansorge, S.; Effects of Nonapeptides Derived From the N-terminal Structure of Human Immunodeficiency Virus-1 (HIV-1) Tat on Suppression of CD26-Dependent T Cell Growth Adv. Exp. Med. Biol. 477, 161-165, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_18

The human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and exerts immunosuppressive effects. Interestingly, Tat inhibits dipeptidyl peptidase IV (DP IV) activity of the T cellactivation marker CD26. The short N-terminal nonapeptideTat(l-9), MDPVDPNIE, also inhibits DP IV activity and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells (PBMC). Here, we present the influence of amino acid exchanges in the first three positions of Tat(l-9). For instance, the replacement of D2 of Tat(l-9) by G or K generated peptides, which inhibit DP IV-catalyzed IL-2(1-12) cleavage nearly threefold stronger. Similar effects were observed on the suppression of DNA synthesis of Tetanus toxoid-stimulated PBMC. This correlation suggests that Tat(l-9)-deduced peptides mediate antiproliferative effects at least in part via specific DP IV interactions and supports the hypothesis that CD26 plays a key role in the regulation of lymphocyte growth.
Bücher und Buchkapitel

Fengler, A.; Brandt, W.; Development and Validation of Homology Models of Human Cathepsins K, S, H, and F Adv. Exp. Med. Biol. 477, 255-260, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_27

Models of the tertiary structures of cathepsins K, S, H, and F were constructed by using homology protein modelling methods and refinements by interactive graphics and energy minimisation. The predicted structures yield information regarding their substrate binding sites and indicate the residues surrounding these sites. The ligandbinding sites were characterised and compared with each other by means of calculated molecular electrostatic surface potentials. This will allow designing and development of new ligands specific for these cathepsins in future investigations.
Bücher und Buchkapitel

Bühling, F.; Fengler, A.; Brandt, W.; Welte, T.; Ansorge, S.; Nagler, D. K.; Review: Novel Cysteine Proteases of the Papain Family Adv. Exp. Med. Biol. 477, 241-254, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_26

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Bücher und Buchkapitel

Brandt, W.; Development of a Tertiary-Structure Model of the C-Terminal Domain of DPP IV Adv. Exp. Med. Biol. 477, 97-101, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_9

Based on the recently published structure of prolyl oligopeptidase (POP) a model of the C-terminal part of dipeptidyl peptidase IV (DPP IV) which contains the active site has been developed. The structure of the model of DPP IV shows considerable similarity to the structure of POP particularly in the active site. A hydrophobic pocket (Tyr666, Tyr670, Tyr 631, Val556) forms the S1-binding site for recognition of proline. Tyr547 may stabilise the oxyanion formed in the tetrahedral intermediates by a strong hydrogen bond. The positively charged N-terminus of ligands of DPP IV is recognised by forming a salt bridge with the acidic side chain Glu668. A second hydrophobic pocket (S2′ to S5′) may represent an important binding site for HIV-1 Tat-protein derivatives, chemokines and others.
Bücher und Buchkapitel

Mrestani-Klaus, C.; Fengler, A.; Faust, J.; Brandt, W.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; N-Terminal HIV-1 Tat Nonapeptides as Inhibitors of Dipeptidyl Peptidase IV. Conformational Characterization Adv. Exp. Med. Biol. 477, 125-129, (2000) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_13

Compared to the N-terminal nonapeptide of the HIV-1 Tat protein as inhibitor of activity of DP IV which is supposed to mediate the immunosuppressive effects of HIV-1 Tat, the Ile5 and Leu6 analogues showed strongly reduced inhibitory activity. Interestingly, replacement of Asp2 with Gly or Lys led to compounds with considerably enhanced inhibition. Therefore, we have applied 1H NMR spectroscopy and restrained molecular dynamics calculations to elucidate the molecular conformation of a series of Tat nonapeptides. Conformational backbone differences of these peptides as well as the nature and the arrangement of the side chains per se at significant positions preventing effective binding to DP IV might explain their different inhibitory activity on DP IV.
Bücher und Buchkapitel

Brandt, W.; A Molecular Model of the Active Site of Dipeptidyl Peptidase IV Adv. Exp. Med. Biol. 421, 171-178, (1997) DOI: 10.1007/978-1-4757-9613-1_22

The ectoenzyme dipeptidyl peptidase IV (DPP IV) is an integral plasma membrane glycoprotein abundantly expressed on a variety of cell surfaces.1 It is a serine peptidase of broad medical and biochemical significance. It plays a role in the degradations and post translational processing of bioactive peptides such as substance P, ß-casomorphins, growth hormone-releasing hormone and promelittin.2–9 DPP IV has been identified as CD26.10 Recently, it could be demonstrated that it is not only a surface differentiation marker involved in the transduction of mitogenic signals in thymocytes and T lymphocytes in human but also a cofactor in AIDS expression.10–13
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