An Oxidative Phenol Coupling Reaction Catalyzed by OxyB, a Cytochrome P450 from the Vancomycin‐Producing Microorganism

Zerbe, Katja; Woithe, Katharina; Li, Dong Bo; Vitali, Francesca; Bigler, Laurent; Robinson, John A.

doi:10.1002/ange.200461278

Cited by 44 publications

(36 citation statements)

References 18 publications

(4 reference statements)

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“…34 An analogous mechanism was proposed, along with a di-radical mechanism, in the ring coupling reaction by the CYP OxyB in the biosynthesis of the vancomycin family of antibiotics. 38, 39 …”

Section: Resultsmentioning

confidence: 99%

Complexity Generation in Fungal Polyketide Biosynthesis: A Spirocycle-Forming P450 in the Concise Pathway to the Antifungal Drug Griseofulvin

et al. 2013

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Griseofulvin (1) is a spirocyclic fungal natural product used in treatment of fungal dermatophytes. Formation of the spirocycle, or the grisan scaffold, from a benzophenone precursor is critical for the activity of 1. In this study, we have systematically characterized each of the biosynthetic enzymes related to the biogenesis of 1, including the characterization of a new polyketide synthase GsfA that synthesize the benzophenone precursor and a cytochrome P450 GsfF that performs oxidative coupling between the orcinol and the phloroglucinol rings to yield the grisan structure. Notably, the finding of GsfF is in sharp contrast to the copper-dependent dihydrogeodin oxidase that performs a similar reaction in the geodin biosynthetic pathway. The biosynthetic knowledge enabled the in vitro total biosynthesis of 1 from malonyl-CoA using all purified enzyme components. This work therefore completely maps out the previously unresolved enzymology of the biosynthesis of a therapeutically relevant natural product

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Section: Resultsmentioning

confidence: 99%

Complexity Generation in Fungal Polyketide Biosynthesis: A Spirocycle-Forming P450 in the Concise Pathway to the Antifungal Drug Griseofulvin

et al. 2013

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“…Because ferredoxin and the ferredoxin:NADP + reductase from the PL producer were not available, we used spinach ferredoxin and the spinach ferredoxin:NADP + reductase in the in vitro assay. [18][19][20] High concentrations of NADPH and NADP + and an efficient NADPH regenerating system were used. [18] Incubations were performed with an extract containing PL D and PL D2.…”

Section: Studies On the Function Of Plao5mentioning

confidence: 99%

Functions of Genes and Enzymes Involved in Phenalinolactone Biosynthesis

et al. 2010

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Phenalinolactones are novel terpene glycoside antibiotics produced by Streptomyces sp. Tü6071. Inactivation of three oxygenase genes (plaO2, plaO3 and plaO5), two dehydrogenase genes (plaU, plaZ) and one putative acetyltransferase gene (plaV) led to the production of novel phenalinolactone derivatives (PL HS6, PL HS7, PL HS2 and PL X1). Furthermore, the exact biosynthetic functions of two enzymes were determined, and their in vitro activities were demonstrated. PlaO1, an Fe(II)/alpha-ketoglutarate-dependent dioxygenase, is responsible for the key step in gamma-butyrolactone formation, whereas PlaO5, a cytochrome P450-dependent monooxygenase, catalyses the 1-C-hydroxylation of phenalinolactone D. In addition, stable isotope feeding experiments with biosynthetic precursors shed light on the origin of the carbons in the gamma-butyrolactone moiety.

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“…7–9 Robinson and colleagues recapitulated the enzymatic activity of OxyB in vitro by showing that it installs the first cross-link between rings C and D (Figure 1). 10,11 Recent studies on the biosynthesis of teicoplanin, a GPA related to vancomycin, have afforded new insights into aryl ether bond formation as well. 12,13 However, since the original studies by Robinson 10 years ago, cross-link formation by additional vancomycin Oxy enzymes has not been accomplished, and a number of questions, including the timing of chlorination and whether the remaining two Oxy enzymes are at all functional in vitro , remain unanswered.…”

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confidence: 99%

In Vitro Reconstitution of OxyA Enzymatic Activity Clarifies Late Steps in Vancomycin Biosynthesis

et al. 2017

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Studies on the biosynthesis of glycopeptide antibiotics have provided many insights into the strategies that Nature employs to build architecturally strained molecules. A key structural feature of vancomycin, the founding member of this class, is a set of three aromatic cross-links that are introduced via yet unknown mechanisms. Previous reports have identified three cytochrome P450 enzymes involved in this process and demonstrated enzymatic activity for OxyB, which installs the first aromatic cross-link. However, the activities of the remaining two P450 enzymes have not been recapitulated. Herein, we show that OxyA generates the second bis-aryl ether bond in vancomycin and that it exhibits strict substrate specificity toward the chlorinated, OxyB-cross-linked product. No OxyA product is detected with the unchlorinated substrate. Together with previous results, these data suggest that chlorination occurs after OxyB- but before OxyA-catalyzed cross-link formation. Our results have important implications for the chemo-enzymatic synthesis of vancomycin and its analogs.

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An Oxidative Phenol Coupling Reaction Catalyzed by OxyB, a Cytochrome P450 from the Vancomycin‐Producing Microorganism

Cited by 44 publications

References 18 publications

Complexity Generation in Fungal Polyketide Biosynthesis: A Spirocycle-Forming P450 in the Concise Pathway to the Antifungal Drug Griseofulvin

Complexity Generation in Fungal Polyketide Biosynthesis: A Spirocycle-Forming P450 in the Concise Pathway to the Antifungal Drug Griseofulvin

Functions of Genes and Enzymes Involved in Phenalinolactone Biosynthesis

In Vitro Reconstitution of OxyA Enzymatic Activity Clarifies Late Steps in Vancomycin Biosynthesis

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