Bacterial Synthesis of Diverse Indole Terpene Alkaloids by an Unparalleled Cyclization Sequence

Xu, Zhongli; Baunach, Martin; Ding, Ling; Hertweck, Christian

doi:10.1002/anie.201204087

Cited by 122 publications

(99 citation statements)

References 31 publications

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“…During characterisation of metabolites from marine Streptomyces, Zhang et al re-isolated the previously discovered xiamycin A (Figure 11, Compound 33), alongside a series of novel N-C and N-N linked xiamycin dimers, 76 compounds also detected in parallel studies by Hertweck et al [77][78][79] Though atropisomeric N-N axes have been observed between sp 2 -hybridized nitrogen atoms in synthetic studies, 80 this discovery marked the first incidence of a naturally-occurring atropdiastereomeric N-N axis between sp 3 -hybridized carbazole nitrogens. The formulae of two atropdiastereomeric compounds were determined to be C 46 H 48 N 2 O 6 using HR-FAB/MS (highresolution fast atom bombardment), corresponding to a dimer of xiamycin A.…”

Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

“…78 Analysis of the 1 H-NMR spectrum of the unnamed dimer revealed it to be asymmetric by the presence of two sets of peaks, resulting in a total of eleven aromatic protons. The absence of a H 21 peak and the presence of a peak corresponding to H 21 ' suggested a C-N linkage at C 21 , which was further supported by 1 H-COSY and HMBC experiments.…”

Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

“…The reason for the atropselectivity of this reaction is currently not known, and is complementary to that reported by Zhang. The biosynthetic origins of the dixiamycins have been the subject of several recent studies, 78,79,82,83 such that there is substantial evidence that xiamycin A is derived from the sesquiterpene-bound indole indosespene by the action of the xia gene cluster of Streptomyces species. The exact mechanism for the dimerisation of xiamycin A to dixiamycins has not been fully elucidated, however it has been proposed that dimerisation occurs by a XiaH-mediated radical homocoupling.…”

Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

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A twist of nature – the significance of atropisomers in biological systems

2015

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. (2015). A twist of nature-the significance of atropisomers in biological systems. Natural Product Reports: a journal of current development in bioorganic chemistry, 32 (11), 1562-1583. A twist of nature-the significance of atropisomers in biological systems AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized. AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized.

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Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

Section: Dixiamycins: Atropisomeric N-c and N-n Coupled Dimers From Mmentioning

confidence: 99%

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A twist of nature – the significance of atropisomers in biological systems

2015

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“…Since the P450s and acetyltransferases encoded by the cluster did not seem to be involved in the cyclization reaction, the only possibility appeared to be the gene encoding a putative "integral membrane protein," pyr4 , a protein that consists of 242 amino acid residues. Importantly, homologues of pyr4 are widely distributed among the biosynthetic gene clusters for several meroterpenoids in fungi, as described later, as well as in actinomycetes [ 7 ]. The wide existence of pyr4 homologues suggested that they play an important role in the biosynthesis of meroterpenoids, and may be involved in the cyclization reaction.…”

Section: Pyripyropene Amentioning

confidence: 77%

Meroterpenoids

Matsuda¹,

Abe²

2014

Fungal Biology

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“…Moreover, meroterpenoids are ubiquitous across all domains of life and are a prevalent source of natural product structural diversity in fungi 13 . Among bacteria, biosynthetic pathways to secondary metabolites that incorporate terpene fragments are often difficult to unravel with established terpene biosynthetic concepts 14–16 .…”

mentioning

confidence: 99%

A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

et al. 2017

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Bacterial meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles. We report the discovery of a hitherto unprecedented enzyme-promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases to account for these discrepancies in the merochlorin and napyradiomycin class of meroterpenoid antibiotics, and we demonstrate that the α-hydroxyketone rearrangement is potentially a conserved biosynthetic reaction in this molecular class. The biosynthetic α-hydroxyketone rearrangement was applied in a concise total synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes, and sheds further light on the mechanism of this unifying enzymatic transformation.

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Bacterial Synthesis of Diverse Indole Terpene Alkaloids by an Unparalleled Cyclization Sequence

Cited by 122 publications

References 31 publications

A twist of nature – the significance of atropisomers in biological systems

A twist of nature – the significance of atropisomers in biological systems

Meroterpenoids

A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

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