Semisynthetic Enzymes in Asymmetric Synthesis:  Enantioselective Reduction of Racemic Hydroperoxides Catalyzed by Seleno-Subtilisin

Häring, Dietmar; Schüler, Ellen; Adam, Waldemar; Saha‐Möller, Chantu R.; Schreier, Peter

doi:10.1021/jo981665a

Cited by 42 publications

(16 citation statements)

References 35 publications

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“…The enzyme has also been used for the chiral resolution of alkyl hydroperoxides. It shows opposite selectivity but similar efficiency to that of horseradish peroxidase, despite a completely different mechanism 18…”

Section: Methodsmentioning

confidence: 96%

Selenoglutaredoxin as a Glutathione Peroxidase Mimic

2008

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Glutaredoxin (Grx1) from Escherichia coli is a monomeric, 85-amino-acid-long, disulfide-containing redox protein. A Grx1 variant in which the redox-active disulfide was replaced with a selenocysteine (C11U/C14S) was prepared by native chemical ligation from three fragments as a potential mimic of the natural selenoenzyme glutathione peroxidase (Gpx). Selenoglutaredoxin, like the analogous C14S Grx1 variant, shows weak peroxidase activity. The selenol provides a 30-fold advantage over the thiol, but its activity is four orders of magnitude lower than that of bovine Gpx. In contrast, selenoglutaredoxin is an excellent catalyst for thiol-disulfide exchange reactions; it promotes the reduction of beta-hydroxyethyldisulfide by glutathione with a specific activity of 130 units mg(-1). This value is 1.8 times greater than that of C14S Grx1 under identical conditions, and >10(4) greater than the peroxidase activity of either enzyme. Given the facile reduction of the glutathionyl-selenoglutaredoxin adduct by glutathione, oxidation of the selenol by the alkyl hydroperoxide substrate likely limits catalytic turnover and will have to be optimized to create more effective Gpx mimics. These results highlight the challenge of generating Gpx activity in a small, generic protein scaffold, despite the presence of a well-defined glutathione binding site and the intrinsic advantage of selenium over sulfur derivatives.

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Section: Methodsmentioning

confidence: 96%

Selenoglutaredoxin as a Glutathione Peroxidase Mimic

2008

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“…Such semisynthetic enzymes with their optimized molecular structures for catalysis of certain reactions offer great promise in bioorganic chemistry. So, for instance, selenosubtilisins were successfully used for the enantioselective reduction of alkyl aryl hydroperoxides to the respective alcohols 25, 26. In analogy to glutathione peroxidase 21, 22 and based on the redox chemistry of simple aromatic selenium compounds 27, a catalytic cycle involving selenenic acid (R 1 SeOH), selenenyl sulfide (R 1 SeSR 2 ), and selenol (R 1 SeH, see Scheme ) was proposed 24 and corroborated by nuclear magnetic resonance (NMR) spectroscopy 28, 29, X‐ray crystallography 30, and kinetic studies 31, 32.…”

Section: Introductionmentioning

confidence: 99%

Redox chemistry of organoselenium compounds: Ab initio and density functional theory calculations on model systems for transition states and intermediates of the redox cycle of selenoenzymes

Benková

Kóňa

Gann

et al. 2002

Int J of Quantum Chemistry

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Ab initio [Hartree-Fock (HF)] and density functional theory (B3LYP) ECPcalculations on intermediates and transition states of the reduction of phenylseleninic acid with hydrogen sulfide and of seleninic acid with benzenethiol as models for the species involved in the redox cycle of selenoenzymes are presented. Selenenyl sulfide is found to be the final product of the reduction reaction with sulfides. Further reduction to the selenol requires surmounting a substantial barrier (∼50 kcal mol −1 ). The final step of the redox cycle-oxidation of the selenol by hydrogen peroxide-is strongly exothermic. In case of the unsubstituted derivative H 2 Se three mechanisms for this oxidation are found [concerted and stepwise 1,2-hydrogen and oxygen shift (TS6A, TS6B, resp.) and a four-membered transition state TS6C]. For the oxidation of phenylselenol only TS6A and TS6B are obtained. For nearly all calculated structures the HF wave functions show a triplet instability. In contrast, at the B3LYP level only TS6C has a significant triplet instability. On the basis of QCISD(T)//QCISD results a mechanism involving TS6C seems highly unlikely.

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“…3c). 28 Notably, selenosubtilisin possessed a substrate scope for peroxidase activity analogous to that of subtilisin for hydrolase activity, and this could be used to predict the outcome of peroxide reduction reactions of different substrates. 29 This result highlights a key advantage to using known folds as ArM scaffolds: native function (e.g.…”

Section: Chemical Mutagenesismentioning

confidence: 99%

Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids

Lewis

2015

Current Opinion in Chemical Biology

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Metallopeptide catalysts and artificial metalloenzymes built from peptide scaffolds and catalytically active metal centers possess a number of exciting properties that could be exploited for selective catalysis. Control over metal catalyst secondary coordination spheres, compatibility with library based methods for optimization and evolution, and biocompatibility stand out in this regard. A wide range of unnatural amino acids have been incorporated into peptide and protein scaffolds using several distinct methods, and the resulting unnatural amino acid containing scaffolds can be used to create novel hybrid metal-peptide catalysts. Promising levels of selectivity have been demonstrated for several hybrid catalysts, and these provide a strong impetus and important lessons for the design of and optimization of hybrid catalysts.

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Semisynthetic Enzymes in Asymmetric Synthesis: Enantioselective Reduction of Racemic Hydroperoxides Catalyzed by Seleno-Subtilisin

Cited by 42 publications

References 35 publications

Selenoglutaredoxin as a Glutathione Peroxidase Mimic

Selenoglutaredoxin as a Glutathione Peroxidase Mimic

Redox chemistry of organoselenium compounds: Ab initio and density functional theory calculations on model systems for transition states and intermediates of the redox cycle of selenoenzymes

Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids

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