Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Grandner, Jessica M.; Cacho, Ralph A.; Tang, Yi; Houk, K. N.

doi:10.1021/acscatal.6b01068

Cited by 70 publications

(55 citation statements)

References 44 publications

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“…376 (In passing we note this oxygen-independent route to spirocycles differs from the O 2 -dependent routes, e.g. to griseofulvin (Scheme 25) 136,137 , reflecting independent routes to this geometry-imposing bicyclic unit. ).…”

Section: Concluding Thoughtsmentioning

confidence: 92%

“…The C-O coupling step was studied computationally by Grandner et al, in which they concluded a third, mechanism A, is the most likely and energetically favorable. 137 This is the radical addition mechanism in which the enzyme performs the O-H abstraction on B ring to give 140 , but avoids diradical formation. Direct attack of the phenoxy radical on A ring leads to ring closure and intermediate 141 , subsequent phenolic O-H abstraction by the heme affords 145 .…”

Section: Radical Cyclization Mechanismsmentioning

confidence: 99%

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Oxidative Cyclization in Natural Product Biosynthesis

et al. 2016

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Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this review, we examine the different strategies used by Nature to create new intra-(inter-)-molecular bonds via redox chemistry. The review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG dependent oxygenases and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installation of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of “disappearing” reactive handles. Lastly, oxidative rearrangement of rings systems, including contractions and expansions will be covered.

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Section: Concluding Thoughtsmentioning

confidence: 92%

Section: Radical Cyclization Mechanismsmentioning

confidence: 99%

Oxidative Cyclization in Natural Product Biosynthesis

et al. 2016

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“…A similar coupling mechanism was computationally proposed for the P450 in the griseofulvin pathway. 15 …”

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confidence: 99%

Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A

Liu²,

Zou³

et al. 2016

J. Am. Chem. Soc.

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Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived di-tyrosine piperazine intermediate. Following enzymatic reduction of the P450-crosslinked di-cyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities.

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“…However, the successful conversion of non‐spiro derivatives into spiro compounds led us to search for the deschlorinated spiro compounds ( 25 – 27 , and 28 – 30 ), which were indeed observed in wild‐type and Δ ams16 mutant strains, respectively (Figures S15 and S17). Previously, spiro‐forming enzymes were reported to be involved in the biosynthesis of natural products such as griseofulvin and pyrroindomycins (details about other compounds can be found in Tang et al …”

Section: Methodsmentioning

confidence: 99%

Armeniaspirol Antibiotic Biosynthesis: Chlorination and Oxidative Dechlorination Steps Affording Spiro[4.4]non‐8‐ene

Xie

Hoffmann

et al. 2019

ChemBioChem

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Armeniaspirols are potent antibiotics containing an unusual spiro[4.4]non‐8‐ene moiety. Herein, we describe the cloning and functional analysis of the armeniaspirol biosynthetic gene cluster. Gene‐inactivation studies and subsequent isolation of previously unknown biosynthetic intermediates shed light on intriguing biosynthetic details. Remarkably, deletion of ams15, which encodes a protein bearing a flavin‐binding domain, led to the accumulation of several non‐spiro intermediates with various numbers of chlorine substitutions on the pyrrole moiety. The di‐ and trichloropyrrole species were converted by Streptomyces albus expressing Ams15 into mono‐ and dichlorinated spiro derivatives, respectively. In addition, in vitro conversion of these non‐spiro intermediates into des‐N‐methyl spiro intermediates by the cell lysate of the same recombinant strain proved Ams15 to be responsible for spiro formation through oxidative dehalogenation.

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Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Cited by 70 publications

References 44 publications

Oxidative Cyclization in Natural Product Biosynthesis

Oxidative Cyclization in Natural Product Biosynthesis

Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A

Armeniaspirol Antibiotic Biosynthesis: Chlorination and Oxidative Dechlorination Steps Affording Spiro[4.4]non‐8‐ene

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