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Ajmaline

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Joachim Stockigt – 1st expert on this subject based on the ideXlab platform

  • the molecular architecture of major enzymes from Ajmaline biosynthetic pathway
    Phytochemistry Reviews, 2007
    Co-Authors: Joachim Stockigt, Santosh Panjikar, Martin Ruppert, Leif Barleben, Elke A Loris, Marco Hill

    Abstract:

    The biosynthetic pathway leading to the monoterpenoid indole alkaloid Ajmaline in Rauvolfia serpentiin serpentina is one of the most studied in the field of natural product biosynthesis. Ajmaline has a complex structure which is based on a six-membered ring system harbouring nine chiral carbon atoms. There are about fifteen enzymes involved, including some involving the side reactions of the Ajmaline biosynthetic pathway. All enzymes exhibit pronounced substrate specificity. In the recent years isolation and sequencing of their cDNAs has allowed a detailed sequence analysis and comparison with functionally related and occasionally un-related enzymes. Site-directed mutations of several of the Ajmaline-synthesizing enzymes have been performed and their catalytic residues have been identified. Success with over-expression of the enzymes was an important step for their crystallization and structural analysis by X-ray crystallography. Crystals with sufficient resolution were obtained from the major enzymes of the pathway. Strictosidine synthase has a 3D-structure with a six-bladed β-propeller fold the first time such a fold found in the plant kingdom. Its ligand complexes with tryptamine and secologanin, as well as structure-based sequence alignment, indicate a possible evolutionary relationship to several primary sequence-unrelated structures with this fold. The structure of strictosidine glucosidase was determined and its structure has as a (β/α)8 barrel fold. Vinorine synthase provides the first 3D structure of a member of BAHD enzyme super-family. Raucaffricine glucosidase involved in a side-route of Ajmaline biosynthesis has been crystallized. The Ajmaline biosynthetic pathway is an outstanding example where many enzymes 3D-structure have been known and where there is a real potential for protein engineering to yield new alkaloid.

  • structure and synthesis of a new indole alkaloid 19 s hydroxy nb methylraumacline obtained by the biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth
    Tetrahedron, 1992
    Co-Authors: Hiromitsu Takayama, Shinichiro Sakai, Norio Aimi, Mariko Kitajima, Shinya Suda, Susanne Endreβ, Joachim Stockigt

    Abstract:

    Abstract From the plant cell suspension cultures of Tauwolfia serpentina Benth., which were cultivated in the alkaloid-production medium after feeding of Ajmaline (1), a new indole alkaloid 19- (S)-hydroxy-Nb-methylraumacline (4) was isolated. The structure of 4 first elucidated by spectroscopic analysis was determined by the chemical synthesis from Ajmaline (1).

  • biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth the new indole alkaloids raumacline and n b methylraumacline
    Tetrahedron Letters, 1990
    Co-Authors: Leo Polz, Joachim Stockigt, Hiromitsu Takayama, Naoki Uchida, Norio Aimi, Shinichiro Sakai

    Abstract:

    Two novel indole alkaloids, raumacline (2) and N(b)-methylraumacline (3), were isolated from plant cell cultures of Rauwolfia serpentina Benth. after feeding experiments with the Rauwolfia alkaloid Ajmaline (1). The structures of the new alkaloids were elucidated by spectroscopic methods and chemical synthesis from Ajmaline (1).

Eberhard P. Scholz – 2nd expert on this subject based on the ideXlab platform

  • inhibition of cardiac kv1 5 and kv4 3 potassium channels by the class ia anti arrhythmic Ajmaline mode of action
    Naunyn-schmiedebergs Archives of Pharmacology, 2013
    Co-Authors: Fathima Fischer, Edgar Zitron, Hugo A. Katus, Nadine Vonderlin, Claudia Seyler, Daniel Scherer, Rudiger Becker, Eberhard P. Scholz

    Abstract:

    Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For Ajmaline, inhibitory effects on a variety of cardiac K+ channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of Ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that Ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 μM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that Ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas Ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that Ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of Ajmaline.

  • Class Ia anti-arrhythmic drug Ajmaline blocks HERG potassium channels: mode of action
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
    Co-Authors: Claudia Kiesecker, Edgar Zitron, Sonja Lück, Ramona Bloehs, Eberhard P. Scholz, Sven Kathöfer, Dierk Thomas, Volker A. W. Kreye, Hugo A. Katus, Wolfgang Schoels

    Abstract:

    Ajmaline is a class Ia anti-arrhythmic drug used in several European countries and Japan as first-line treatment for ventricular tachyarrhythmia. Ajmaline has been reported to induce cardiac output (QT) prolongation and to inhibit cardiac potassium currents in guinea pig cardiomyocytes. In order to elucidate the molecular basis of these effects, we examined effects of Ajmaline on human ether a-go-go related gene HERG potassium channels. Electrophysiological experiments were performed with human embryonic kidney (HEK) cells (whole-cell patch clamp) and Xenopus oocytes (double-electrode voltage clamp) expressing wild-type and mutant HERG channels. Ajmaline blocked HERG currents with an IC_50 of 1.0 μmol/l in HEK cells and 42.3 μmol/l in Xenopus oocytes. The onset of block was fast and reached steady-state conditions after 180 s. The inhibitory effect was completely reversible upon wash-out. In HERG mutant channels Y652A and F656A lacking aromatic residues in the S6 domain, the inhibitory effect of Ajmaline was completely abolished. Ajmaline induced a small shift in HERG current half-maximal activation voltage towards more negative potentials. Ajmaline did not markedly affect HERG inactivation. Inhibitory effects were not voltage-dependent. Ajmaline block exhibited positive frequency dependence. Ajmaline blocked HERG channels in the open, but not in the closed states. Binding of Ajmaline to inactivated HERG channels may also be possible. In inactivation-deficient HERG S620T channels, the sensitivity to Ajmaline was markedly reduced. The IC_50 of HERG channel blockade in HEK cells lies within the range of unbound therapeutic plasma concentrations of Ajmaline. Therefore, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of Ajmaline and to its pro-arrhythmic potential.

Shinichiro Sakai – 3rd expert on this subject based on the ideXlab platform

  • structure and synthesis of a new indole alkaloid 19 s hydroxy nb methylraumacline obtained by the biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth
    Tetrahedron, 1992
    Co-Authors: Hiromitsu Takayama, Shinichiro Sakai, Norio Aimi, Mariko Kitajima, Shinya Suda, Susanne Endreβ, Joachim Stockigt

    Abstract:

    Abstract From the plant cell suspension cultures of Tauwolfia serpentina Benth., which were cultivated in the alkaloid-production medium after feeding of Ajmaline (1), a new indole alkaloid 19- (S)-hydroxy-Nb-methylraumacline (4) was isolated. The structure of 4 first elucidated by spectroscopic analysis was determined by the chemical synthesis from Ajmaline (1).

  • biotransformation of Ajmaline in plant cell cultures of rauwolfia serpentina benth the new indole alkaloids raumacline and n b methylraumacline
    Tetrahedron Letters, 1990
    Co-Authors: Leo Polz, Joachim Stockigt, Hiromitsu Takayama, Naoki Uchida, Norio Aimi, Shinichiro Sakai

    Abstract:

    Two novel indole alkaloids, raumacline (2) and N(b)-methylraumacline (3), were isolated from plant cell cultures of Rauwolfia serpentina Benth. after feeding experiments with the Rauwolfia alkaloid Ajmaline (1). The structures of the new alkaloids were elucidated by spectroscopic methods and chemical synthesis from Ajmaline (1).