Acyloin and Benzoin Condensations

Pohl, Martina; Dresen, Carola; Beigi, Maryam; Müller, Michael

doi:10.1002/9783527639861.ch22

Cited by 17 publications

(7 citation statements)

References 155 publications

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“…The natural activity of PDCs and BFD is the decarboxylation of pyruvate and benzoylformate to the respective aldehydes that are liberated upon protonation of the hydroxyethyl‐ThDP or hydroxybenzyl‐ThDP, respectively (Table ). However, if another aldehyde is offered as the acceptor 1,2‐addition yielding α‐hydroxyketones occurs, which is discussed in more detail below (for further details see ).…”

Section: Enzymes From the DC Familymentioning

confidence: 99%

“…An overview of all annotated sequences can be found in the ThDP‐dependent Enzyme Engineering Database (TEED, http://www.teed.uni-stuttgart.de) . Among these, enzymes catalysing the cleavage and formation of C–C bonds have been most intensively studied . Here, the potential to catalyse the formation of mixed carboligation products from a donor substrate and an acceptor substrate in a highly chemoselective and stereoselective manner is of special interest.…”

Section: Introductionmentioning

confidence: 99%

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Engineering stereoselectivity of ThDP-dependent enzymes

Hailes

Rother

Müller

et al. 2013

FEBS J

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Thiamine diphosphate-dependent enzymes are broadly distributed in all organisms, and they catalyse a broad range of C-C bond forming and breaking reactions. Enzymes belonging to the structural families of decarboxylases and transketolases have been particularly well investigated concerning their substrate range, mechanism of stereoselective carboligation and carbolyase reaction. Both structurally different enzyme families differ also in stereoselectivity: enzymes from the decarboxylase family are predominantly R-selective, whereas those from the transketolase family are S-selective. In recent years a key focus of our studies has been on stereoselective benzoin condensation-like 1,2-additions. Meanwhile, several S-selective variants of pyruvate decarboxylase, benzoylformate decarboxylase and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPH-CHC) synthase as well as R-selective transketolase variants were created that allow access to a broad range of enantiocomplementary a-hydroxyketones and a,a′-dihydroxyketones. This review covers recent studies and the mechanistic understanding of stereoselective C-C bond forming thiamine diphosphate-dependent enzymes, which has been guided by structure-function analyses based on mutagenesis studies and from influences of different substrates and organic co-solvents on stereoselectivity.

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Section: Enzymes From the DC Familymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Engineering stereoselectivity of ThDP-dependent enzymes

Hailes

Rother

Müller

et al. 2013

FEBS J

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“…While the decarboxylation of 2-ketoacids [10] and the carboligation of two aldehydes to 2-hydroxy ketones are catalysed by most members of the ThDP-dependent decarboxylases [9], their substrate ranges are different. The well characterised PDC from Saccharomyces cerevisiae , BFD from Pseudomonas putida and BAL from Pseudomonas fluorescence accept a broad variety of substrates [7,11,12], while SEPHCHC-synthase (MenD) is limited to a small number of substrates [13,14]. Additional complexity of C-C bond formation results from the fact that a substrate might be either a donor, which is activated by addition to ThDP in the active site, or an acceptor, which reacts with the ThDP-bound donor, resulting in different products [7,11,12].…”

Section: Introductionmentioning

confidence: 99%

“…The well characterised PDC from Saccharomyces cerevisiae , BFD from Pseudomonas putida and BAL from Pseudomonas fluorescence accept a broad variety of substrates [7,11,12], while SEPHCHC-synthase (MenD) is limited to a small number of substrates [13,14]. Additional complexity of C-C bond formation results from the fact that a substrate might be either a donor, which is activated by addition to ThDP in the active site, or an acceptor, which reacts with the ThDP-bound donor, resulting in different products [7,11,12]. Reactions catalysed by members of the structural group of ThDP-dependent decarboxylases include decarboxylation of 2-keto acids, synthesis of various chiral 2-hydroxy ketones by asymmetric benzoin- [11,15] and cross-benzoin condensation [16,17], the racemic resolution of 2-hydroxy ketones via C-C bond cleavage [18], and Stetter-like reactions, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Additional complexity of C-C bond formation results from the fact that a substrate might be either a donor, which is activated by addition to ThDP in the active site, or an acceptor, which reacts with the ThDP-bound donor, resulting in different products [7,11,12]. Reactions catalysed by members of the structural group of ThDP-dependent decarboxylases include decarboxylation of 2-keto acids, synthesis of various chiral 2-hydroxy ketones by asymmetric benzoin- [11,15] and cross-benzoin condensation [16,17], the racemic resolution of 2-hydroxy ketones via C-C bond cleavage [18], and Stetter-like reactions, e.g. the addition of decarboxylated 2-ketoglutyrate to isochorismate by MenD [19].…”

Section: Introductionmentioning

confidence: 99%

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A standard numbering scheme for thiamine diphosphate-dependent decarboxylases

et al. 2012

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BackgroundStandard numbering schemes for families of homologous proteins allow for the unambiguous identification of functionally and structurally relevant residues, to communicate results on mutations, and to systematically analyse sequence-function relationships in protein families. Standard numbering schemes have been successfully implemented for several protein families, including lactamases and antibodies, whereas a numbering scheme for the structural family of thiamine-diphosphate (ThDP) -dependent decarboxylases, a large subfamily of the class of ThDP-dependent enzymes encompassing pyruvate-, benzoylformate-, 2-oxo acid-, indolpyruvate- and phenylpyruvate decarboxylases, benzaldehyde lyase, acetohydroxyacid synthases and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase (MenD) is still missing.Despite a high structural similarity between the members of the ThDP-dependent decarboxylases, their sequences are diverse and make a pairwise sequence comparison of protein family members difficult.ResultsWe developed and validated a standard numbering scheme for the family of ThDP-dependent decarboxylases. A profile hidden Markov model (HMM) was created using a set of representative sequences from the family of ThDP-dependent decarboxylases. The pyruvate decarboxylase from S. cerevisiae (PDB: 2VK8) was chosen as a reference because it is a well characterized enzyme. The crystal structure with the PDB identifier 2VK8 encompasses the structure of the ScPDC mutant E477Q, the cofactors ThDP and Mg2+ as well as the substrate analogue (2S)-2-hydroxypropanoic acid. The absolute numbering of this reference sequence was transferred to all members of the ThDP-dependent decarboxylase protein family. Subsequently, the numbering scheme was integrated into the already established Thiamine-diphosphate dependent Enzyme Engineering Database (TEED) and was used to systematically analyze functionally and structurally relevant positions in the superfamily of ThDP-dependent decarboxylases.ConclusionsThe numbering scheme serves as a tool for the reliable sequence alignment of ThDP-dependent decarboxylases and the unambiguous identification and communication of corresponding positions. Thus, it is the basis for the systematic and automated analysis of sequence-encoded properties such as structural and functional relevance of amino acid positions, because the analysis of conserved positions, the identification of correlated mutations and the determination of subfamily specific amino acid distributions depend on reliable multisequence alignments and the unambiguous identification of the alignment columns. The method is reliable and robust and can easily be adapted to further protein families.

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