Biosynthesis of the Tetracyclines

Hošťálek, Z.; Ванек, З.

doi:10.1007/978-3-642-70304-1_4

Cited by 7 publications

(7 citation statements)

References 106 publications

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“…The interconversion between 5(5a)dehydrotetracycline (2b) and 5a(11a)-dehydrotetracycline (2a) is supported by a D−H exchange experiment, where the 5-H peak is eliminated over time at 300 K (Figure S2) in methanol-d 4 . Despite this interconversion, only the 5(5a)-dehydrotetracycline isomer (2b), and not the 5a(11a)dehydrotetracycline form (2a), was observed in the 1 H and 13 C NMR spectra, implying that 5(5a)-dehydrotetracycline (2b) is the prevalent isomer (Scheme 1). The 1 H and 13 C assignments of 5(5a)-dehydrotetracycline (2b) are supported by one-and two-dimensional NMR experiments (Figure 2…”

Section: ■ Resultsmentioning

confidence: 99%

“…The scaffolds for semisynthetic modifications to chlortetracycline, oxytetracycline, tetracycline, and demeclocycline. 13 The use of alternative original hosts such as the dactylocycline producer Dactylosporangium sp. SC 14051 is theoretically possible but practically limited, because of a very slow growth rate and an inaccessibility of genetic modifications.…”

Section: ■ Introductionmentioning

confidence: 99%

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Heterologous Catalysis of the Final Steps of Tetracycline Biosynthesis by Saccharomyces cerevisiae

et al. 2021

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Developing treatments for antibiotic resistant bacterial infections is among the highest priority public health challenges worldwide. Tetracyclines, one of the most important classes of antibiotics, have fallen prey to antibiotic resistance, necessitating the generation of new analogs. Many tetracycline analogs have been accessed through both total synthesis and semisynthesis, but key C-ring tetracycline analogs remain inaccessible. New methods are needed to unlock access to these analogs, and heterologous biosynthesis in a tractable host such as Saccharomyces cerevisiae is a candidate method. C-ring analog biosynthesis can mimic nature’s biosynthesis of tetracyclines from anhydrotetracyclines, but challenges exist, including the absence of the unique cofactor F420 in common heterologous hosts. Toward this goal, this paper describes the biosynthesis of tetracycline from anhydrotetracycline in S. cerevisiae heterologously expressing three enzymes from three bacterial hosts: the anhydrotetracycline hydroxylase OxyS, the dehydrotetracycline reductase CtcM, and the F420 reductase FNO. This biosynthesis of tetracycline is enabled by OxyS performing just one hydroxylation step in S. cerevisiae despite its previous characterization as a double hydroxylase. This single hydroxylation enabled us to purify and structurally characterize a hypothetical intermediate in oxytetracycline biosynthesis that can explain structural differences between oxytetracycline and chlortetracycline. We show that Fo, a synthetically accessible derivative of cofactor F420, can replace F420 in tetracycline biosynthesis. Critically, the use of S. cerevisiae for the final steps of tetracycline biosynthesis described herein sets the stage to achieve a total biosynthesis of tetracycline as well as novel tetracycline analogs in S. cerevisiae with the potential to combat antibiotic-resistant bacteria.

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Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Heterologous Catalysis of the Final Steps of Tetracycline Biosynthesis by Saccharomyces cerevisiae

et al. 2021

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“…published that CtcP, formerly known as Chl or Cts4, catalyzes the chlorination of tetracycline as the last step in the biosynthesis of 7‐chlortetracycline (Scheme ) . This finding is in absolute disagreement with the isolation of 7‐chloro‐5a(11a)‐dehydrotetracycline, 6‐demethylchlortetracycline, and especially with 4‐oxoanhydrochlortetracycline (Scheme ) . If chlorination is the last step in the biosynthesis of 7‐chlortetracycline, the existence of these compounds cannot be explained.…”

Section: New Developmentsmentioning

confidence: 99%

“… Chlorination of tetracycline to form 7‐chlortetracycline by the flavin‐dependent halogenase CtcP (also named Cts4 or Chl) and a few chlorinated 7‐chlortetracycline derivatives, whose existence cannot be explained if chlorination is the last step in the biosynthesis of 7‐chlortetracycline …”

Section: New Developmentsmentioning

confidence: 99%

Specific Enzymatic Halogenation—From the Discovery of Halogenated Enzymes to Their Applications In Vitro and In Vivo

2016

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During the last 20 years, focus has shifted from haloperoxidases to flavin-dependent and non-heme-iron halogenases because of their proven involvement in the biosynthesis of halogenated metabolites in different organisms and the regioselectivity of their reactions. During the first 10-12 years, the main research topics were the detection of halogenases as well as the elucidation of three-dimensional structures and reaction mechanisms. This Review mainly deals with studies on halogenating enzymes published between 2010 and 2015. It focusses on the elucidation of the involvement of halogenating enzymes in halometabolite biosynthesis, application of halogenases in in vivo and in vitro systems, in vivo modification of biosynthetic pathways in bacteria and plants, improvement of enzyme stability, broadening of substrate specificity, and the combination of biocatalysis with chemical synthesis to produce new compounds.

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“…In a stimulative hypothesis entitled BHow many genes are needed for the biosynthesis of chlortetracycline ( Vaněk et al 1971;Hošťálek and Vaněk 1985), the biosynthetic process leading to tetracyclines was divided into several parts of metabolic pathways, one part leading from glucose to pyruvate, another part of its transformation to acetyl-CoA and formation of a hypothetical tricyclic nonaketide, and the part of enzymatic reactions leading to the final product, i.e., chlortetracycline. This last part of biosynthesis was proposed to represent a chain of 11 enzymatic steps, compiled on the principles of logical chemical reactions.…”

Section: Tetracyclinesmentioning

confidence: 99%

Biogenesis of antibiotics—viewing its history and glimpses of the future

et al. 2016

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This review aims at comparing some historical data with the current situation in the study of biogenesis of natural compounds, antibiotics in the first place. Biogenesis of tetracyclines and cycloheximide and related compounds serves as example. Examples of molecular biological and bioinformatics methods used in the study of antibiotic biogenesis are described both in terms of its historical aspects and the current knowledge.

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Biosynthesis of the Tetracyclines

Cited by 7 publications

References 106 publications

Heterologous Catalysis of the Final Steps of Tetracycline Biosynthesis by Saccharomyces cerevisiae

Heterologous Catalysis of the Final Steps of Tetracycline Biosynthesis by Saccharomyces cerevisiae

Specific Enzymatic Halogenation—From the Discovery of Halogenated Enzymes to Their Applications In Vitro and In Vivo

Biogenesis of antibiotics—viewing its history and glimpses of the future

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