cis‐Dihydroxylation of Tricyclic Arenes and Heteroarenes Catalyzed by Toluene Dioxygenase: A Molecular Docking Study and Experimental Validation

Derek Boyd, Narain D. Sharma, Ian Brannigan, Christopher McGivern, Peter Nockemann, Paul Stevenson, Colin McRoberts, Patrick Hoering, Christopher C.R. Allen

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Molecular docking studies of toluene dioxygenase (TDO) led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using P. putida UV4 whole cells expressing TDO, confirmed that both angular and lateral cis‐dihydroxylation occurred in the predicted regioselective and stereoselective manner. The TDO‐catalysed (P. putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite (> 80% yield). 2‐Hydroxydibenzofuran, resulting from dehydration of 1,2‐dihydrodibenzofuran‐1,2‐diol, was also found to undergo cis‐ dihydroxylation to give a very minor cis‐dihydrodiol metabolite (< 2% yield). The enantiopurity (>98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by formation of diMTPA ester derivatives and X‐ray crystallography of a diol epoxide derivative. The cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products. dioxygenase‐catalysed cis‐dihydroxylation of substituted phenol and aniline substrates with Pseudomonas putida UV4, yielded arene cis‐dihydrodiol metabolites which tautomerised to the preferred cyclohex‐2‐en‐1‐one cis‐diols, as predicted by molecular docking studies. Further metabolism of cyclohex‐2‐en‐1‐one cis‐diols, under similar conditions, formed 4‐hydroxycyclohex‐2‐en‐1‐ones, as a new type of phenol metabolite
Original languageEnglish
JournalAdvanced Synthesis & Catalysis
Early online date18 Mar 2019
DOIs
Publication statusEarly online date - 18 Mar 2019

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Metabolites
Phenol
Derivatives
Crystallography
Epoxy Compounds
Substrates
Biological Products
Dehydration
Metabolism
Esters
Cells
toluene dioxygenase
dibenzofuran
Biotransformation

Cite this

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title = "cis‐Dihydroxylation of Tricyclic Arenes and Heteroarenes Catalyzed by Toluene Dioxygenase: A Molecular Docking Study and Experimental Validation",
abstract = "Molecular docking studies of toluene dioxygenase (TDO) led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using P. putida UV4 whole cells expressing TDO, confirmed that both angular and lateral cis‐dihydroxylation occurred in the predicted regioselective and stereoselective manner. The TDO‐catalysed (P. putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite (> 80{\%} yield). 2‐Hydroxydibenzofuran, resulting from dehydration of 1,2‐dihydrodibenzofuran‐1,2‐diol, was also found to undergo cis‐ dihydroxylation to give a very minor cis‐dihydrodiol metabolite (< 2{\%} yield). The enantiopurity (>98{\%} ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by formation of diMTPA ester derivatives and X‐ray crystallography of a diol epoxide derivative. The cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products. dioxygenase‐catalysed cis‐dihydroxylation of substituted phenol and aniline substrates with Pseudomonas putida UV4, yielded arene cis‐dihydrodiol metabolites which tautomerised to the preferred cyclohex‐2‐en‐1‐one cis‐diols, as predicted by molecular docking studies. Further metabolism of cyclohex‐2‐en‐1‐one cis‐diols, under similar conditions, formed 4‐hydroxycyclohex‐2‐en‐1‐ones, as a new type of phenol metabolite",
author = "Derek Boyd and Sharma, {Narain D.} and Ian Brannigan and Christopher McGivern and Peter Nockemann and Paul Stevenson and Colin McRoberts and Patrick Hoering and Allen, {Christopher C.R.}",
year = "2019",
month = "3",
day = "18",
doi = "10.1002/adsc.201900147",
language = "English",
journal = "Advanced Synthesis and Catalysis",
issn = "1615-4150",
publisher = "Wiley-VCH Verlag",

}

cis‐Dihydroxylation of Tricyclic Arenes and Heteroarenes Catalyzed by Toluene Dioxygenase: A Molecular Docking Study and Experimental Validation. / Boyd, Derek; Sharma, Narain D.; Brannigan, Ian; McGivern, Christopher; Nockemann, Peter; Stevenson, Paul; McRoberts, Colin; Hoering, Patrick; Allen, Christopher C.R.

In: Advanced Synthesis & Catalysis, 18.03.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - cis‐Dihydroxylation of Tricyclic Arenes and Heteroarenes Catalyzed by Toluene Dioxygenase: A Molecular Docking Study and Experimental Validation

AU - Boyd, Derek

AU - Sharma, Narain D.

AU - Brannigan, Ian

AU - McGivern, Christopher

AU - Nockemann, Peter

AU - Stevenson, Paul

AU - McRoberts, Colin

AU - Hoering, Patrick

AU - Allen, Christopher C.R.

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Molecular docking studies of toluene dioxygenase (TDO) led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using P. putida UV4 whole cells expressing TDO, confirmed that both angular and lateral cis‐dihydroxylation occurred in the predicted regioselective and stereoselective manner. The TDO‐catalysed (P. putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite (> 80% yield). 2‐Hydroxydibenzofuran, resulting from dehydration of 1,2‐dihydrodibenzofuran‐1,2‐diol, was also found to undergo cis‐ dihydroxylation to give a very minor cis‐dihydrodiol metabolite (< 2% yield). The enantiopurity (>98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by formation of diMTPA ester derivatives and X‐ray crystallography of a diol epoxide derivative. The cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products. dioxygenase‐catalysed cis‐dihydroxylation of substituted phenol and aniline substrates with Pseudomonas putida UV4, yielded arene cis‐dihydrodiol metabolites which tautomerised to the preferred cyclohex‐2‐en‐1‐one cis‐diols, as predicted by molecular docking studies. Further metabolism of cyclohex‐2‐en‐1‐one cis‐diols, under similar conditions, formed 4‐hydroxycyclohex‐2‐en‐1‐ones, as a new type of phenol metabolite

AB - Molecular docking studies of toluene dioxygenase (TDO) led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using P. putida UV4 whole cells expressing TDO, confirmed that both angular and lateral cis‐dihydroxylation occurred in the predicted regioselective and stereoselective manner. The TDO‐catalysed (P. putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite (> 80% yield). 2‐Hydroxydibenzofuran, resulting from dehydration of 1,2‐dihydrodibenzofuran‐1,2‐diol, was also found to undergo cis‐ dihydroxylation to give a very minor cis‐dihydrodiol metabolite (< 2% yield). The enantiopurity (>98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by formation of diMTPA ester derivatives and X‐ray crystallography of a diol epoxide derivative. The cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products. dioxygenase‐catalysed cis‐dihydroxylation of substituted phenol and aniline substrates with Pseudomonas putida UV4, yielded arene cis‐dihydrodiol metabolites which tautomerised to the preferred cyclohex‐2‐en‐1‐one cis‐diols, as predicted by molecular docking studies. Further metabolism of cyclohex‐2‐en‐1‐one cis‐diols, under similar conditions, formed 4‐hydroxycyclohex‐2‐en‐1‐ones, as a new type of phenol metabolite

U2 - 10.1002/adsc.201900147

DO - 10.1002/adsc.201900147

M3 - Article

JO - Advanced Synthesis and Catalysis

JF - Advanced Synthesis and Catalysis

SN - 1615-4150

ER -