Glycosyltransferases and Other Tailoring Enzymes as Tools for the Generation of Novel Compounds

Bechthold, Andreas; Weitnauer, Gabriele; Luzhetskyy, Andriy; Berner, M.; Bihlmeier, C.; Boll, Raija; Dürr, Clemens; Frerich, Anke; Hofmann, Carsten; Mayer, Almuth; Treede, Irina; Vente, Andreas; Luzhetskyy, M.

doi:10.1007/3-540-27055-8_7

Cited by 3 publications

(1 citation statement)

References 23 publications

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“…It has been shown that four glycosyltransferases are needed for the biosynthesis of the hexasaccharide side chain of landomycin A and for the biosynthesis of urdamycin A 6–8. In addition, the function of each glycosyltransferase in both pathways has been determined 7–13. The angucyclic cores of landomycin A and urdamycin B differ in several respects.…”

Section: Introductionmentioning

confidence: 99%

Pyrolo[1,2:4,5]‐1,4‐dioxopyrazino[1,2:1,6]pyrido[3,4‐b]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry‐Dependent Activity

et al. 2011

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Antifibrinolytic agents are required during complex surgeries to decrease bleeding; their pro-thrombotic potency and efficacy in causing hemostasis has attracted much attention. To discover new inhibitors of urokinase with high selectivity for antifibrinolytic effects over pro-thrombotic effects, the 12-position of (5aS,12S,14aS)- and (5aS,12R,14aS)-5,14-dioxo-1,2,3,5,5a,6,11, 12,14,14a-decahydro-5H,14H-pyrolo[1,2:4,5]pyrazino[1,2:1,6]pyrido[3,4-b]indoles were modified with L-Ala, L-Asp, L-Phe, L-Trp, L-Lys, L-Ser, Gly, and L-Leu to provide 16 (5aS,12S,14aS) and (5aS,12R,14aS) derivatives. In a murine bleeding model, the (5aS,12S,14aS) derivatives containing L-Ala, L-Asp, L-Phe, and L-Trp induced blood coagulation for the treated mice; they also stimulated thrombus formation in a rat thrombosis model, but the other derivatives inhibited thrombosis. The most potent compound, the L-Asp derivative, showed a good therapeutic window: the minimum effective dose for coagulation was <1 nmol kg(-1), whereas at 10 nmol kg(-1), no pro-thrombotic effect was observed. This type of coagulation action was correlated with a mechanism of urokinase inhibition, and these results could lead to the discovery of novel urokinase inhibitors.

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Section: Introductionmentioning

confidence: 99%

Pyrolo[1,2:4,5]‐1,4‐dioxopyrazino[1,2:1,6]pyrido[3,4‐b]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry‐Dependent Activity

et al. 2011

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LanV, a Bifunctional Enzyme: Aromatase and Ketoreductase during Landomycin A Biosynthesis

et al. 2005

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LanV is involved in the biosynthesis of landomycin A. The exact function of this enzyme was elucidated with combinatorial biosynthesis by using Streptomyces fradiae mutants that produce urdamycin A. After expression of lanV in S. fradiae DeltaurdM, which is a mutant that accumulates rabelomycin, urdamycinon B and urdamycin B were found to be produced by the strain. This result indicates that LanV is involved in the 6-ketoreduction of the angucycline core, which preceeds a 5,6-dehydration reaction. 9-C-D-Olivosyltetrangulol was also produced by this strain; this demonstrates that LanV catalyses the aromatization of ring A of the angucycline structure. Coexpression of lanV and lanGT2 in S. fradiae AO, a mutant that lacks all four urdamycin glycosyltransferases, resulted in the production of tetrangulol and the glycoside landomycin H, both of which have an aromatic ring A. As glycosylated angucyclines were not observed after expression of lanGT2 in the absence of lanV, we conclude that LanGT2 needs an aromatized ring A for substrate recognition.

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Type II PKS

Rohr

Hertweck

2010

Comprehensive Natural Products II

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Glycosyltransferases and Other Tailoring Enzymes as Tools for the Generation of Novel Compounds

Cited by 3 publications

References 23 publications

Pyrolo[1,2:4,5]‐1,4‐dioxopyrazino[1,2:1,6]pyrido[3,4‐b]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry‐Dependent Activity

Pyrolo[1,2:4,5]‐1,4‐dioxopyrazino[1,2:1,6]pyrido[3,4‐b]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry‐Dependent Activity

LanV, a Bifunctional Enzyme: Aromatase and Ketoreductase during Landomycin A Biosynthesis

Type II PKS

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