Phylogenetic Studies, Gene Cluster Analysis, and Enzymatic Reaction Support Anthrahydroquinone Reduction as the Physiological Function of Fungal 17β‐Hydroxysteroid Dehydrogenase

Fürtges, Leon; Conradt, David; Schätzle, Michael A.; Singh, Savitri; Kraševec, Nada; Rižner, Tea Lanišnik; Müller, Michael; Husain, Syed Masood

doi:10.1002/cbic.201600489

Cited by 13 publications

(28 citation statements)

References 29 publications

(65 reference statements)

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“…To ascertain the generality of these results and to obtain monomeric intermediates and flavoskyrin‐type dimeric compounds of other unprotected anthraquinones, we envisaged the synthesis of 2,2′‐ epi ‐cytoskyrin A ( 21 ) starting from monomeric lunatin ( 9 ). Lunatin ( 9 ) has already been proposed as being involved in the biosynthesis of cytoskyrin A . Both lunatin and (+)‐cytoskyrin A have been isolated from the fungus C. lunata and their biosynthesis could involve PHAR for the reduction of lunatin hydroquinones 10 a / 10 b .…”

Section: Figurecontrasting

confidence: 89%

“…Compound 3 is formed by the reduction of tautomers of emodin hydroquinone by NADPH‐dependent MdpC (from the monodictyphenone biosynthetic gene cluster of A. nidulans ), which on elimination of water results in the formation of chrysophanol ( 2 ). The same transformation is catalyzed by analogous enzymes, AflM from Aspergillus parasiticus and ‘17β‐hydroxysteroid dehydrogenase“ (17β‐HSDcl) from Cochliobolus lunatus , which further led to the elucidation of deoxygenation steps in aflatoxin B 1 and cladofulvin biosynthesis …”

Section: Figurementioning

confidence: 99%

“…We hypothesized that 4 a can be formed by oxidation of reduced emodin hydroquinone 3 . To test our hypothesis, we used 17β‐HSDcl, synonymous with polyhydroxyanthracene reductase (PHAR), from the filamentous fungus Curvularia lunata (teleomorph C. lunatus ) to convert emodin ( 1 ) into 3 . Emodin ( 1 ) on incubation with Na 2 S 2 O 4 resulted in a tautomeric mixture of emodin hydroquinones 8 a / 8 b , which after reduction with PHAR in the presence of NADPH gave reduced emodin hydroquinone 3 in 75 % yield (see the Supporting Information and Scheme ).…”

Section: Figurementioning

confidence: 99%

“…[10] Compound 3 is formed by the reduction of tautomers of emodin hydroquinone by NADPH-dependentM dpC (from the monodictyphenone biosynthetic gene cluster of A. nidulans), which on elimination of waterr esults in the formationo fc hrysophanol ( 2). The same transformationi sc atalyzed by analogous enzymes, AflM from Aspergillus parasiticus [11] and '17b-hydroxysteroid dehydrogenase" (17b-HSDcl) from Cochliobolus lunatus, [12] which further led to the elucidation of deoxygenation steps in aflatoxinB 1 [11] and cladofulvin biosynthesis. [13] Another related biosynthetic intermediate, dihydroemodin (4a), has been proposeda sb eing involved in the biosynthesis of (À)-flavoskyrin (5)a nd (À)-rugulosin (6), isolated from P. islandicum,a nd (+ +)-rugulosin (7), isolated from P. rugulosum.…”

mentioning

confidence: 99%

“…We hypothesized that 4a can be formed by oxidation of reduced emodin hydroquinone 3.T ot est our hypothesis, we used 17b-HSDcl, synonymous with polyhydroxyanthracene reductase (PHAR), from the filamentous fungus Curvularial unata (teleomorph C. lunatus)t oc onvert emodin (1)i nto 3. [12] Emodin (1)o ni ncubation with Na 2 S 2 O 4 resulted in at automeric mixture of emodinh ydroquinones 8a/8b,w hich after reductionw ith PHAR in the presence of NADPH gave reduced emodinh ydroquinone 3 in 75 %y ield (see the Supporting Information and Scheme 1). In this transformation,N ADPH was regenerated using ag lucose/glucose dehydrogenase system.T oo btain 4a from 3,w ef irst applied MnO 2 for oxidation, which mainly resulted in the formation of chrysophanol (2), with no trace of monomeric intermediate (4a).…”

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confidence: 99%

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Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

Saha

Mondal

Witte

et al. 2018

Chemistry A European J

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Modified bisanthraquinones are complex dimeric natural products containing a cage-like structural motif. For their biosynthesis, monomeric dihydroanthraquinones have been proposed as key intermediates despite not being isolated from natural sources or synthesized as of yet. Here, isolation and characterization of dihydroemodin, as well as dihydrolunatin, synthesized by a biomimetic and chemoenzymatic approach using NADPH-dependent polyhydroxyanthracence reductase (PHAR) from Cochliobolus lunatus followed by Pb(OAc) oxidation is reported. Subsequent dimerization through a hetero-Diels-Alder reaction of the dihydroemodin and dihydrolunatin resulted in (-)-flavoskyrin (68 %) and (-)-lunaskyrin (62 %), respectively. Pyridine treatment of (-)-flavoskyrin and (-)-lunaskyrin gave (-)-rugulosin and (-)-2,2'-epi-cytoskyrin A in 64 % and 60 % yield, respectively, through a cascade that involves two dimeric intermediates. Implications of the described synthesis for the biosynthesis of bisanthraquinones by a combination of enzymatic and spontaneous steps are discussed.

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Section: Figurecontrasting

confidence: 89%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

Saha

Mondal

Witte

et al. 2018

Chemistry A European J

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Multi‐faceted Set‐up of a Diverse Ketoreductase Library Enables the Synthesis of Pharmaceutically‐relevant Secondary Alcohols

et al. 2021

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Enzymes are valuable tools to introduce chirality into small molecules. Especially, ketoreductase (KRED)-catalyzed transformations of ketones to yield chiral secondary alcohols have become an established biocatalytic process step in the pharmaceutical and fine chemical industry. Development time, however, remains a critical factor in chemical process development and thus, the competitiveness of a biocatalytic reaction step is often governed by the availability of off-the-shelf enzyme libraries. To expand the biocatalytic toolbox with additional ketoreductases, we established a multi-faceted screening procedure to capture KRED diversity from different sources, such as literature, available genome data, and uncharacterized microbial strains. Overall, we built a library consisting of 51 KRED enzymes, 29 of which have never been described in literature before. Notably, 18 of the newly described enzymes exhibited anti-Prelog preference complementing the majority of ketoreductases which generally follow Prelog's rule. Analysis of the library's catalytic activity toward a chemically diverse ketone substrate set of pharmaceutical interest further highlighted the broad substrate scope and the complementing enantio-preference of the individual KREDs. Using the generated sequence-function data of the included short chain dehydrogenases in a bioinformatic analysis led to the identification of possible sequence determinants of the stereospecificity exhibited by these enzymes.

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A Biomimetic Synthesis of Racemic Dihydroanthracen‐1(2H)‐ones Using Sodium Borohydride in Water

et al. 2020

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Herein, we report a single step synthesis of racemic dihydroanthracenones by the reduction of anthraquinones using NaBH 4 and Na 2 S 2 O 4 in water. The racemic mixture is utilized to determine the enantiomeric excess for the chiral dihydroanthracenones reportedly synthesized by the chemoenzymatic reduction of anthraquinones. The results show > 99% ee for the Dihydroanthracenones are recognised as putative biosynthetic precursors involved in the biosynthesis of deoxyanthraquinones and modified bisanthraquinones in fungi. [1,2] Despite not being isolated from natural sources as yet, the chiral dihydroanthracenones are synthesized using two completely different approaches and are used in the synthesis of modified bisanthraquinones. In the very first approach, Nicolaou and coworkers achieved the total synthesis of protected (S)-configured dihydroanthracenones 4, 5 by the Hauser annulation between MOM protected nitrile 1 or 2 and MOM protected enone 3, respectively (Figure 1a). [3,4] Both 4 and 5 are then being used as precursors towards the synthesis of naturally occurring dimeric bisanthraquinones, (+)-rugulosin (6) and (+)-2,2′-epi-cytoskyrin A (7) (Figure 1a). [3] However, the requirement of a large number of steps to synthesize 1-3 involving extensive protection and deprotection of hydroxyl groups makes this approach less attractive for the synthesis of dihydroanthracenones. As an alternate Müller and co-workers have identified a fungal enzyme, MdpC of Aspergillus nidulans, using which the putative biosynthetic intermediates, (R)-configured dihydroanthracenones were synthesized chemoenzymatically using anthraquinones. [5] For example, (R)-3,8,9,10-tetrahydroxy-6-methyl-3,4-dihydroanthracen-1(2H)-one (9) is synthesized by MdpC-catalyzed reduction of emodin hydroquinones 13a/13b [formed in situ by the reduction of emodin (8) in the presence of Na 2 S 2 O 4 ] using NADPH as a cofactor in buffer (Figure 1b). [5] Other enzymes which also catalyze the same transformation include PHAR of Cochliobolus [a] A.Scheme 2. Proposed retrosynthetic route for the preparation of racemic dihydroanthracenones based on the procedure reported by Nicolaou and co-workers. [3] Eur.

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Phylogenetic Studies, Gene Cluster Analysis, and Enzymatic Reaction Support Anthrahydroquinone Reduction as the Physiological Function of Fungal 17β‐Hydroxysteroid Dehydrogenase

Cited by 13 publications

References 29 publications

Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

Multi‐faceted Set‐up of a Diverse Ketoreductase Library Enables the Synthesis of Pharmaceutically‐relevant Secondary Alcohols

A Biomimetic Synthesis of Racemic Dihydroanthracen‐1(2H)‐ones Using Sodium Borohydride in Water

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