A Tailor‐Made Chimeric Thiamine Diphosphate Dependent Enzyme for the Direct Asymmetric Synthesis of (<i>S</i>)‐Benzoins

Westphal, Robert; Vogel, Constantin; Schmitz, C.; Pleiss, Jürgen; Müller, Michael; Pohl, Martina; Rother, Dörte

doi:10.1002/anie.201405069

Cited by 35 publications

(30 citation statements)

References 17 publications

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“…In syntheses in which aldehydes other than glycolaldehyde are used as acceptors, formation of the desired product will be competing with the one‐substrate reaction. Active‐site engineering as pioneered by Pohl for a range of ThDP‐dependent enzymes could ensure that glycolaldehyde will be the donor molecule in mixed carbo‐ligation reactions …”

Section: Resultsmentioning

confidence: 99%

Separating Thermodynamics from Kinetics—A New Understanding of the Transketolase Reaction

et al. 2017

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Transketolase catalyzes asymmetric C−C bond formation of two highly polar compounds. Over the last 30 years, the reaction has unanimously been described in literature as irreversible because of the concomitant release of CO2 if using lithium hydroxypyruvate (LiHPA) as a substrate. Following the reaction over a longer period of time however, we have now found it to be initially kinetically controlled. Contrary to previous suggestions, for the non‐natural conversion of synthetically more interesting apolar substrates, the complete change of active‐site polarity is therefore not necessary. From docking studies it was revealed that water and hydrogen‐bond networks are essential for substrate binding, thus allowing aliphatic aldehydes to be converted in the charged active site of transketolase.

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Section: Resultsmentioning

confidence: 99%

Separating Thermodynamics from Kinetics—A New Understanding of the Transketolase Reaction

et al. 2017

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“…It had been concluded that the shape of the binding site determines the steric orientation of the acceptor aldehyde moieties in ThDP‐dependent decarboxylases . Accordingly, several variants were designed, such as a PDC from Acetobacter pasteurianus for the synthesis of ( S )‐benzoins or a PDC from Zymomonas mobilis for the synthesis of ( S )‐acetoin and ( S )‐PAC . Thus, analyzing functionally relevant positions is a promising and robust strategy for the prediction of the effect of enzyme variants in further studies.…”

Section: Discussionmentioning

confidence: 99%

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

et al. 2019

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Thiamine diphosphate‐dependent decarboxylases catalyze both cleavage and formation of CC bonds in various reactions, which have been assigned to different homologous sequence families. This work compares 53 ThDP‐dependent decarboxylases with known crystal structures. Both sequence and structural information were analyzed synergistically and data were analyzed for global and local properties by means of statistical approaches (principle component analysis and principal coordinate analysis) enabling complexity reduction. The different results obtained both locally and globally, that is, individual positions compared with the overall protein sequence or structure, revealed challenges in the assignment of separated homologous families. The methods applied herein support the comparison of enzyme families and the identification of functionally relevant positions. The findings for the family of ThDP‐dependent decarboxylases underline that global sequence identity alone is not sufficient to distinguish enzyme function. Instead, local sequence similarity, defined by comparisons of structurally equivalent positions, allows for a better navigation within several groups of homologous enzymes. The differentiation between homologous sequences is further enhanced by taking structural information into account, such as BioGPS analysis of the active site properties or pairwise structural superimpositions. The methods applied herein are expected to be transferrable to other enzyme families, to facilitate family assignments for homologous protein sequences.

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“…Three ThDP‐dependent enzymes have been used to catalyze the homocoupling of benzaldehyde on preparative scale: namely the benzoyl formate decarboxylase from Pseudomonas putida ( Pp BFD), the benzaldehyde lyase from Pseudomonas fluorescens Biovar I ( Pf BAL), and a variant of the pyruvate decarboxylase from Acetobacter pasteurianus Ap PDC‐Glu469Gly/Thr384Gly/Ile468Ala/Trp543Phe . The BFD catalyzes the non‐oxidative decarboxylation of benzoylformate and plays its natural role in mandelate catabolism.…”

Section: Benzoin Reactionmentioning

confidence: 99%

“…The moderate enantioselectivity was then enhanced further by shaping the acceptor binding site through mutation of Ile468 and Trp534, two residues that contribute to stabilizing the parallel orientation of the aromatic acceptor ( R pathway). Their exchange afforded the highly S ‐specific four‐point mutant ApPDC‐Glu469Gly/Thr384Gly/Ile468Ala/Trp534Phe, which gave ( S )‐benzoin [( S )‐ 3 ] in 66 % yield and 98 % ee as well as other benzoin analogues, especially meta ‐substituted ones, with very high ee values (Table , columns 7 and 8) …”

Section: Benzoin Reactionmentioning

confidence: 99%

Thiamine‐Diphosphate‐Dependent Enzymes as Catalytic Tools for the Asymmetric Benzoin‐Type Reaction

2016

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Benzoin-type reactions allow the generation of α- hydroxy ketones through the (formal) carboligation of two alde- hyde reactants. The synthetic relevance of the products and the wide distribution of the α-hydroxy ketone functionality in bioactive natural compounds have provided the motivation for intensive research efforts directed towards the development of ever more efficient and selective catalysts for reactions of this class. As in many other areas of study, the solution developed in nature – that is, the utilization of thiamine-diphosphate-dependent (ThDP-dependent) enzymes – also in this case allows levels of chemo- and stereoselectivity currently unattainable by biomimetic organocatalysts to be achieved. Here we present an overview of the structural diversity of the α-hydroxy ketone motif achievable through ThDP-dependent enzyme catalysis. Details relating to structure–activity relationships and to ra- tional mutagenesis approaches for improving the catalytic per- formances of wild-type enzymes are also illustrated

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A Tailor‐Made Chimeric Thiamine Diphosphate Dependent Enzyme for the Direct Asymmetric Synthesis of (S)‐Benzoins

Cited by 35 publications

References 17 publications

Separating Thermodynamics from Kinetics—A New Understanding of the Transketolase Reaction

Separating Thermodynamics from Kinetics—A New Understanding of the Transketolase Reaction

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

Thiamine‐Diphosphate‐Dependent Enzymes as Catalytic Tools for the Asymmetric Benzoin‐Type Reaction

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