Novel Key Metabolites Reveal Further Branching of the Roquefortine/Meleagrin Biosynthetic Pathway

Ries, Marco; Ali, Hazrat; Lankhorst, Peter P.; Hankemeier, Thomas; Bovenberg, Roel A. L.; Driessen, Arnold J. M.; Vreeken, Rob J.

doi:10.1074/jbc.m113.512665

Cited by 51 publications

(67 citation statements)

References 21 publications

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“…Gene inactivation experiments revealed that the rearrangement reaction that forms the triazaspirocyclic skeleton proceeds via a nitrone intermediate, named roquefortine L ( 67 ). 204 Flavin-dependent monooxygenase RoqM was identified as the enzyme responsible for nitrone installation because ΔroqM mutants did not produce 70 and 71 , and instead accumulated 69 . Furthermore, gene inactivation of roqO , which encodes a predicted P450 monooxygenase, suggested that this enzyme could catalyze a requisite oxidation at C 16 on 67 to promote the rearrangement reaction to the triazaspirocycle ( 72 → 70 ).…”

Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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“…22 More recently, a rigorous structural elucidation of the metabolites of this pathway prompted a revision of the biosynthetic mechanism for this particular rearrangement. 35 The key revision to this newly proposed metabolic pathway is the generation of the nitrone-bearing intermediate roquefortine L ( 7 ) by RoqM from 1 (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30

et al. 2016

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Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective nitrones. This work describes the first implementation of a nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products.

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“…Fungi are particularly useful microorganisms in fermentation as they produce an array of diverse natural products, many of which have potential as therapeutic agents. Roquefortine C has been a compound of interest for a number of years due to its structural complexity and uniqueness (Shangguan et al, 2008) and also for its role as a biosynthetic precursor to a number of biologically active related metabolites (Ali et al, 2013; Garcia-Estrada et al, 2011; Han et al, 2013; Koizumi et al, 2004; Kosalkova et al, 2015; Reshetilova et al, 1995; Ries et al, 2013; Zheng et al, 2013). Using roquefortine C as a model compound, we have developed an experiment to introduce undergraduate students to the fields of fermentation and complex natural products.…”

Section: Introductionmentioning

confidence: 99%

Incorporating Fermentation into Undergraduate Laboratory Courses

Gober

Joullié

2015

AJS

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Laboratory courses in universities have a responsibility to introduce current research practices and trends in scientific research to adequately prepare students for work in the field. One such research practice gaining popularity in recent years is that of green chemistry. Since the 1960s, increasing concern over the release of toxic chemicals into the environment has led to a push for more environmentally responsible chemistry. A growing faction of chemists has begun to adopt methods to eliminate chemical waste and support green chemistry. Fermentation is an ideal technique to demonstrate environmentally sustainable chemistry in an undergraduate laboratory class. Fermentation of complex natural products, as opposed to traditional organic synthesis, is beneficial as it supports a number of principles of green chemistry; it is conducted at ambient temperature and pressure, uses inexpensive and innocuous materials, makes use of renewable resources, and does not require a fume hood. Skills implemented during fermentation can be easily taught to upper-level Chemistry and Biochemistry undergraduate students, who typically have limited exposure to complex natural products in their coursework. Such a course would be interdisciplinary in nature, incorporating fungal biology and metabolism as well as organic chemistry. Students would learn a variety of skills, including growth media selection and preparation, inoculation of fungal cultures, extraction of natural products, and purification and characterization of metabolites. Experiments of this nature would allow for discussions of several areas of research: green chemistry, natural products and their application to medicine, identification of functional groups in complex molecules by spectroscopy, and introduction to biochemistry and metabolism. Roquefortine C, a prenylated indole alkaloid readily produced by a variety of species of Penicillia, is an excellent candidate for demonstrating fermentation in a laboratory classroom setting, owing to its ease of purification from other metabolites and its unique structural features.

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Novel Key Metabolites Reveal Further Branching of the Roquefortine/Meleagrin Biosynthetic Pathway

Cited by 51 publications

References 21 publications

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30

Incorporating Fermentation into Undergraduate Laboratory Courses

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