The Substrate Spectrum of Mandelate Racemase: Minimum Structural Requirements for Substrates and Substrate Model

Felfer, Ulfried; Goriup, Marian; Koegl, Marion F.; Wagner, Ulrike; Larissegger‐Schnell, Barbara; Faber, Kurt; Kroutil, Wolfgang

doi:10.1002/adsc.200505012

Cited by 50 publications

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“…[3] We have recently shown that mandelate racemase [EC 5.1.2.2] from Pseudomonas putida ATCC 12633 is an excellent catalyst for the isomerization of a wide spectrum of b,g-unsaturated a-hydroxycarboxylic acids. [4] However, saturated (aliphatic) analogues were not accepted at all. This limitation was successfully overcome by the use of whole resting cells of Lactobacillus spp., which allowed the clean racemization of a wide range of aliphatic and aryl-aliphatic a-hydroxycarboxylic acids.…”

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Biocatalytic Racemization of α‐Hydroxy Ketones (Acyloins) at Physiological Conditions using Lactobacillus paracasei DSM 20207

2006

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Abstract:Biocatalytic racemization of open-chain and cyclic dialkyl-, alkyl-aryl-and diaryl-substituted acyloins was accomplished using whole resting cells of Lactobacillus paracasei DSM 20207. The mild (physiological) reaction conditions ensured the suppression of undesired side reactions, such as elimination or condensation. This novel biocatalytic isomerization protocol represents an essential tool for the deracemization of pharmacologically important building blocks.Keywords: acyloins; biotransformations; Lactobacillus; racemization Until recently, the entropy-driven isomerization of enantiomers -racemization -was generally considered as an unwanted side reaction rather than a synthetically useful transformation. As a consequence, the controlled racemization of organic compounds has been studied rather scarcely and the number of protocols available to date using mild reaction conditions is very small.[1]The importance of clean racemization processes for organic synthesis predominantly emerged from their key role in so-called deracemization processes, [2] which allow the transformation of a racemate into a single stereoisomeric product without the occurrence of an unwanted stereoisomer in 100% theoretical yield. Since the majority of chemical racemization protocols require harsh reaction conditions, they are incompatible with an (in-situ) enantioselective biocatalytic transformation. In contrast, enzymes are highly compatible with each other and biocatalytic racemization thus holds great potential. [3] We have recently shown that mandelate racemase [EC 5.1.2.2] from Pseudomonas putida ATCC 12633 is an excellent catalyst for the isomerization of a wide spectrum of b,g-unsaturated a-hydroxycarboxylic acids.[4] However, saturated (aliphatic) analogues were not accepted at all. This limitation was successfully overcome by the use of whole resting cells of Lactobacillus spp., which allowed the clean racemization of a wide range of aliphatic and aryl-aliphatic a-hydroxycarboxylic acids. [5] In order to broaden the portfolio of biocatalytic racemization, we envisaged to extend the substrate range towards other hydroxy-compounds -acyloins. Non-racemic a-hydroxy ketones [6] constitute popular building blocks for the synthesis vic-diols and amino alcohols through diastereoselective reduction/alkylation and reductive amination, respectively, with highly efficient chirality transfer.[7] Chemical racemization of acyloins usually proceeds through the corresponding enediol and thus predominantly features methods based on acid-or base-catalysis.[8] The latter are often plagued by elimination as a major side reaction due to the ease of formation of a resonance-stabilized conjugated enone. Our search for a biocatalytic racemization of acyloins was triggered by the speculative (but unproven) existence of an acetoin racemase [9] and benzoin racemase, respectively. [10] In order to cover a reasonably broad range of substrates, enantiopure acyloins 1 -6 bearing small and large groups at both ends were selected for our initial tests...

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Biocatalytic Racemization of α‐Hydroxy Ketones (Acyloins) at Physiological Conditions using Lactobacillus paracasei DSM 20207

2006

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“…[311] In Bezugnehmend auf ein oben bereits ausführlich diskutiertes Beispiel werden in Lit. [314] interessante Fortschritte bei der Entwicklung einer effizienten Mandelatracemase vorgestellt. In Lit.…”

Section: Verfahrenskonzepte Unter Berücksichtigung Der Racemisierungunclassified

Verfahren zur Enantiomerentrennung

Lorenz

Seidel‐Morgenstern

2014

Angewandte Chemie

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Die Verfügbarkeit reiner Enantiomere ist von steigender Bedeutung für die pharmazeutische Industrie sowie auch für die Agrochemie und Biotechnologie. Generell gibt es zwei konkurrierende Ansätze zur Gewinnung von reinen Enantiomeren. Der “chirale” Ansatz basiert auf der Entwicklung einer asymmetrischen Synthese, die selektiv eines der Enantiomere liefert. Der “racemische” Ansatz basiert auf der Trennung eines Gemischs der beiden Enantiomere, wobei hier in den letzten Jahren bemerkenswerte Fortschritte erzielt werden konnten. Dieser Aufsatz fokussiert insbesondere auf enantioselektive Kristallisationsprozesse und präparative Chromatographie, einschließlich hybrider Trennprozesse und der zusätzlichen Integration von Racemisierungsschritten. Zur Illustration dienen mehrere in unserem Arbeitskreis untersuchte Trennungen.

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“…[5] We have recently shown that mandelate racemase [EC 5.1.2.2] from Pseudomonas putida ATCC 12633 is an excellent biocatalyst for the racemization of a wide spectrum of β,γ-unsaturated α-hydroxycarboxylic acids. [6] The substrate spectrum of mandelate racemase has been found to be remarkably wide and encompasses various types of β,γ-unsaturated α-hydroxycarboxylic acids, such as substituted (hetero)aryl mandelic acid [7] (or amide) [8] analogues and even cyclic and open-chain 2-hydroxy-3-butenoic acid derivatives. However, aliphatic and aryl-aliphatic α-hydroxycarboxylic acids, which are unable to stabilize the α-carbanion intermediate formed during enzymatic racemization, turned out to be non-substrates.…”

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confidence: 99%

“…However, aliphatic and aryl-aliphatic α-hydroxycarboxylic acids, which are unable to stabilize the α-carbanion intermediate formed during enzymatic racemization, turned out to be non-substrates. [6] In order to circumvent this limitation of mandelate racemase regarding its inability to interconvert the enantiomers of aliphatic and aryl-aliphatic α-hydroxycarboxylic acids, a matching α-hydroxyacid racemase activity was sought. Based on early reports on the lactate racemase activity of halophilic Archaea, anaerobic rumen bacteria and Lactobacillus spp., a screening recently provided a set of lactic acid bacteria that are able to racemize a broad spectrum of aliphatic and aryl-aliphatic α-hydroxycarboxylic acids at fair rates.…”

Section: Introductionmentioning

confidence: 99%

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

et al. 2006

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The biocatalytic racemization of a range of (hetero)aryl-and (di)aryl-aliphatic α-hydroxycarboxylic acids has been achieved by using whole resting cells of Lactobacillus spp. The essentially mild (physiological) reaction conditions ensure the suppression of undesired side reactions, such as elimination, decomposition or condensation. Cofactor/inhibitor studies using a cell-free extract of Lactobacillus paracasei DSM 20207 reveal that the addition of redox cofactors

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The Substrate Spectrum of Mandelate Racemase: Minimum Structural Requirements for Substrates and Substrate Model

Cited by 50 publications

References 50 publications

Biocatalytic Racemization of α‐Hydroxy Ketones (Acyloins) at Physiological Conditions using Lactobacillus paracasei DSM 20207

Biocatalytic Racemization of α‐Hydroxy Ketones (Acyloins) at Physiological Conditions using Lactobacillus paracasei DSM 20207

Verfahren zur Enantiomerentrennung

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

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