Transaminases for the synthesis of enantiopure beta-amino acids
© Rudat et al; licensee Springer. 2012
Received: 20 January 2012
Accepted: 31 January 2012
Published: 31 January 2012
Optically pure β-amino acids constitute interesting building blocks for peptidomimetics and a great variety of pharmaceutically important compounds. Their efficient synthesis still poses a major challenge. Transaminases (also known as aminotransferases) possess a great potential for the synthesis of optically pure β-amino acids. These pyridoxal 5'-dependent enzymes catalyze the transfer of an amino group from a donor substrate to an acceptor, thus enabling the synthesis of a wide variety of chiral amines and amino acids. Transaminases can be applied either for the kinetic resolution of racemic compounds or the asymmetric synthesis starting from a prochiral substrate. This review gives an overview over microbial transaminases with activity towards β-amino acids and their substrate spectra. It also outlines current strategies for the screening of new biocatalysts. Particular emphasis is placed on activity assays which are applicable to high-throughput screening.
Since the discovery of transamination in biological systems (Braunstein and Kritzmann 1937Moyle Needham 1930) the significance of transaminases (TAs) for amino acid metabolism has been the subject of intensive research. Over the last 15 years, TAs have gained increasing attention in organic synthesis for the biocatalytic production of a wide variety of chiral amines and α-amino acids. This has been discussed in detail in a series of excellent reviews (Höhne and Bornscheuer 2009; Koszelewski et al. 2010; Taylor et al. 1998; Ward and Wohlgemuth 2010). Advantages in the use of TAs lie in mostly low-cost substrates, no necessity for external cofactor recycling and the enzymes' high enantioselectivity and reaction rate. For the synthesis of enantiopure β-amino acids only a limited number of TAs are available. Therefore efficient screening techniques for TAs with high activities as well as broader substrate specificity and different enantioselectivities are crucial for the successful application of transaminases for the synthesis of β-amino acids. Of particular interest are methods that can be used at small scale compatible with microtiter plates.
A plethora of chemical approaches have been established to produce chiral β-amino acids including (1) the resolution of racemic β-amino acids, (2) the use of naturally occurring chiral α-amino acids, and (3) asymmetric synthesis (Liu and Sibi 2002). As resolutions of racemic mixtures are complex and time-consuming procedures, the chiral pool of natural α-amino acids is limited and catalysts or chiral auxiliaries cause high costs, all of these strategies have their limitations when applied on an industrial scale (Weiner et al. 2010).
Several enzymes have successfully been tested to produce enantiopure β-amino acids from different starting compounds (for an overview see Liljeblad and Kanerva 2006). Most strategies resemble kinetic resolutions of N-acylated or esterified β-amino acids by hydrolytic enzymes, e.g. lipases (Tasnádi et al. 2008). Although industrially applied for certain products, this strategy is limited to a maximum yield of 50%, and so is the recently tested β-amino acid synthesis via Bayer-Villiger monooxygenases (Rehdorf et al. 2010). As the latter enzymes are cofactor (NADPH) dependent, these processes rely on cofactor recycling which is achieved by whole cell biotransformations, assumingly leading to side products as well as transport limitations depending on the substrate which moreover needs to be N-protected.
Various aminomutases have been used for the conversion of aliphatic and aromatic α-amino acids to the corresponding β-isomers (for an overview see Wu et al. 2010a). Coupling the catalysis of a promiscuous alanine racemase with that of phenylalanine aminomutase (PAM) increased the production of enantiopure (R)-β-arylalanines from the corresponding racemic α-isomers (Cox et al. 2009). Using PAM in tandem with a phenylalanine ammonia lyase (PAL), various aromatic (S)-β-amino acids can be obtained (Wu et al. 2010b). These latter studies deal with one potential pitfall of utilizing these enzymes which lies in the reaction's equilibrium and the thus limited final yields of the desired products. Another limitation for application in industry is the usually low activity, leading to quite slow conversions. Moreover, many otherwise promising aminomutases require multiple expensive cofactors and strictly anaerobic conditions Wu et al. 2010a.
A modification of the well established hydantoinase process is investigated for the production of enantiopure β-amino acids from dihydropyrimidine derivatives (Engel et al. 2011). The stereoselective hydrolysis of racemic phenyldihydrouracil to D- and L-N-carbamoyl-β-phenylalanine was shown which can be further hydrolyzed to the corresponding β-amino acid. However, at the moment this process lacks a suitable racemase (or alternatively an efficient chemical racemization) to gain a 100% yield.
In conclusion, even though several chemical and enzymatic routes (and chemo-enzymatic tandems) are applied and under intense investigation, there still is no gold standard for the preparation of enantiopure β-amino acids.
Formally, the reaction catalyzed by TAs can be considered a redox reaction with the oxidative deamination of the donor in conjunction with the reductive amination of the acceptor. The reaction is divided into two half-reactions obeying a ping-pong bi-bi mechanism. TAs belong to the large and diverse group of pyridoxal phosphate (PLP)-dependent enzymes and are ubiquitous in living organisms playing an important role in amino acid metabolism (Christen and Metzler 1985Cooper and Meister 1989; Taylor et al. 1998). So far only the reaction mechanism of aspartate transaminase (EC 18.104.22.168) has been studied extensively, which is assumed to be typical of pyridoxal-5'-phosphate dependent transaminases (Frey and Hegeman 2007Shin and Kim 2002). The reaction starts with the deamination of aspartate to α-ketoglutarate. In the resting enzyme PLP is covalently bound to the ε-amino group of a lysine (Lys258) in the active site of the apoenzyme forming the internal aldimine. Upon contact with the substrate, the bond between cofactor and apoenzyme dissolves, and PLP forms a Schiff base with the substrate (= the external aldimine). The free ε-amino group of Lys258 then acts as a catalyst for the 1,3-prototropic shift to form the ketimine. The ketimine is hydrolyzed to yield the keto acid and PMP. The following second half reaction consists of the formation of glutamate from α-ketoglutarate. Following the same reaction steps in reverse, the internal aldimine is regenerated (Eliot and Kirsch 2004Hayashi et al. 2003).
Classification of transaminases
Protein subfamilies of TAs according to Pfam; abbreviations: α-KG = α-ketoglutaric acid, PYR = pyruvate.
I and II
β-TA from Mesorhizobium sp. LUK
α-KG or PYR
branched-chain amino-acid TA
Substrate spectra of TAs showing activity towards β-amino acids
Transaminases from wild-type microorganisms
Comparison of the substrate spectra of selected ω-TAs.
aliphatic β-amino acid
aromatic β-amino acid
Pseudomonas sp. F-126
(Yonaha et al. 1976; Yonaha et al. 1977)
Moraxella lacunata WZ34
Alcaligenes denitrificans Y2k-2
V. fluvialis JS17
Arthrobacer sp. KNK168
Mesorhizobium LUK sp.
Mesorhizobium loti MAFF303099
Variovorax sp. JH2
Variovorax sp. BC114
Burkholderia sp. BS115
Only a small number of TAs with high activity towards aromatic β-amino acids have been described (s. Table 2) and only two sequences, from the TA of the soil bacterium Mesorhizobium sp. LUK (GenBank: ABL74379.1) (Kim et al. 2007) and from the ω-TA Ml0107 from M. loti MAFF303099 (GenBank: NP_101976.1) (Kwon et al. 2010), have been elucidated and published to date. The TA from Mesorhizobium sp. LUK shows, as reported by the authors, the highest identity (53%) and similarity (66%) to a glutamate-1-semialdehyde 2,1-aminomutase of Polaromonas sp. strain JS666. Taking into consideration sequences which were submitted to Genbank since the publication of this article, the comparison of this amino acid sequence using blastp gives a putative aminotransferase class III from Variovorax paradoxus S110 (Gene ID: :7970445) as the closest match with 52% identities and 69% similarity. Interestingly, of the other transaminases reported to act on β-phenylalanine, one belongs to the species V. paradoxus (Banerjee et al. 2005) and two to the genus Variovorax (Brucher et al. 2010Mano et al. 2006). The preliminary X-ray structure of the TA from Mesorhizobium sp. LUK has been published recently (Kim 2011).
Wild-type ω-TAs almost universally exhibit (S)-selectivity. Notable exceptions are the ω-TA of Arthrobacter sp. KNK168 (Iwasaki et al. 2003Iwasaki et al. 2006) and its homolog, the commercially available ATA-117 (Codexis Inc.) as well as the TA from Alcaligenes eutrophus (Banerjee et al. 2005) 59. Svedendahl and coworkers (2010) could invert the enantioselectivity of an (S)-selective ω-TA from Arthrobacter citreus by single point mutation for their model substrate 4-fluorophenylacetone. This change in enantioselectivity was substrate-dependent. Whether or not this approach proves to be useful for the inversion of enantioselectivity of other TAs, remains to be seen.
Protein design of TAs for a modified or expanded substrate spectrum
Both rational design and directed evolution have been employed with the aim to enhance the activity of TAs towards aryl-β-amino acids 25. Hwang and coworkers (2004) reported the directed evolution of the ω-TA from V. fluvialis by error-prone PCR in order to increase activity towards β-phenylalanine. The best mutant exhibited a threefold activity increase in the conversion of β-phenylalanine compared to the wild-type. However, the yield of the transamination of β-phenylalanine was below 5% in 20 h. The same group later modified an ω-TA from Caulobacter crescentus which exhibited high activities towards short, aliphatic β-amino acids by site-directed mutagenesis (Hwang et al. 2008). A 3D model was constructed by homology modeling using a dialkylglycine decarboxylase as a template. This led to a threefold increase in activity for β-phenylalanine. Compared to the over 100-fold higher activity towards short, aliphatic β-amino acids, this is still quite low.
Screening strategies for microbial TAs acting on β-amino acids
Enrichment culture and in-silico screening
The first directed screenings for microorganisms exhibiting TA activity towards β-amino acids were performed by enrichment culture using the desired β-amino acid as a major or the sole nitrogen source. Toyama et al. (Toyama et al. 1973) isolated the strain Pseudomonas sp. F-126 by enrichment culture from soil using a medium containing β-alanine. Further studies revealed it to possess an ω-amino acid:pyruvate TA with high activity towards β-alanine and other ω-amino acids (Yonaha et al. 1976). With a similar approach most of the currently known TAs with activity towards β-amino acids were discovered. As the sequence-function relationship among TAs is as of yet poorly understood, enrichment culture still constitutes the greatest source of new TAs active towards β-amino acids.
However, some attempts have been made to identify interesting TAs from the ever growing number of completely sequenced genomes. Kaulmann et al. (2007) used the sequence of the ω-TA from V. fluvialis for the in silico screening of novel TAs. They cloned and purified a putative TA from Chromobacterium violaceum which showed a similar substrate spectrum as the one from V. fluvialis. In a similar approach the previously described TA from Caulobacter crescentus was identified using the sequence of an ω-TA from Alcaligenes denitrificans as a template (Hwang et al. 2008). The novel TA exhibited high activities towards short, aliphatic β-amino acids and aromatic amines. Recently, Kwon et al. (Kwon et al. 2010) established the cell-free expression of computationally predicted putative ω-TAs, which circumvents cloning and expression procedures. As part of this study, the putative ω-TA Ml0107 from M. loti MAFF303099 was identified based on its sequence homology with the previously described TAs from Caulobacter crescentus and V. fluvialis. ω-TA Ml0107 exhibited activity to β-phenylalanine, 1-aminoindane and benzylamine.
The sequences of the two TAs with high activity towards aromatic β-amino acids (TA from Mesorhizobium sp. LUK (Kim et al. 2007), ω-TA Ml0107 from M. loti MAFF303099 (Kwon et al. 2010)) have, to the best of our knowledge, so far not been used for in-silico screening.
Activity assays for high-throughput screening
The first assay was realized by Hwang et al. (2004). It is based on the formation of a blue amino acid-copper complex by the α-amino acid produced in the TA reaction and a CuSO4/MeOH staining solution (see Figure 3a). The assay was tested using a great variety of aliphatic and aromatic β-amino acids as amino donors with good accuracy. Furthermore, by using both enantiomers of an amino donor separately, information on the enantiopreference of the studied enzyme could be gained. A disadvantage of this method consists in the fact that the staining solution inhibits the enzyme, so that it can only be applied as an end-point measurement. Additionally, this method does not allow the use of cell extracts as free α-amino acids disturb the reaction. Thus, enzyme purification is necessary. Therefore the application of this assay is rather limited. Coupling the determination of TA activity with driving the reaction to completion, Truppo et al. (2009) developed an elegant multi-enzymatic system for the HTP-screening and scale-up of TA catalyzed reactions (see Figure 3b). In this system, pyruvate which is generated through the TA reaction is reduced to L-lactate by a lactate dehydrogenase (LDH). Recycling of the LDH cofactor NADH by glucose dehydrogenase (GDH) ultimately leads to the formation of gluconic acid and thus to a pH drop. The progression of the reaction can be measured by monitoring the change of absorbance of a pH indicator (phenol red). This system proved to be especially useful for rapid scale-up. While the system was only tested with ketones as substrate, theoretically β-keto acids could also be employed. Limits of the reaction are that only pyruvate dependent TAs can be tested, no information on the enantioselectivity or enantiopreference of the studied enzyme can be gained and that as it is a multi-enzymatic system, reaction conditions can only be altered marginally. Additionally, most β-keto acids are instable due to spontaneous decarboxylation. A potential solution to this crucial problem is discussed in the conclusion section. A simple assay for the screening of ω-TAs has been developed by Schätzle et al. (2009). The assay is based on the transamination of the model substrate α-methylbenzylamine to acetophenone (see Figure 3c). Acetophenone exhibits high absorbance around 245 nm. While this assay does not directly screen for activity towards β-amino acids, α-methylbenzylamine constitutes a good model substrate for ω-TAs which also possess activity towards short-chain aliphatic β-amino acids. Advantages of this assay are its applicability to cell extracts, the possibility to determine the enantiopreference by using enantiopure α-methylbenzylamine and its high sensitivity. The same group recently published another assay which allows the determination of amino donor specificity (see Figure 3d) (Schätzle et al. 2010). The principle of the assay differs from all other presented methods as it measures the change of conductivity of the reaction mixture. The progression of the reaction results in a decrease of conductivity as charged compounds (a positively charged amine and a negatively charged keto acid) are converted to non-conducting products (a non-charged ketone and a zwitterionic amino acid). Advantages of this assay are the broad spectra of amino donors and amino acceptors which can be used and its high sensitivity. Yet the mode of analysis itself makes the simultaneous measurement of many samples cumbersome as each reaction tube or well would have to be equipped with an electrode. This conductivity assay should also work using a β-keto acid instead of an α-keto acid, leading to the zwitterionic β-amino acid and an uncharged ketone. However, the potential spontaneous decarboxylation of the charged β-keto acid to an uncharged compound might lead to some conductivity decrease even without TA activity. Hopwood et al. (2011) recently described a multi-enzymatic reaction system employing an amino acid oxidase which converts the co-product of the transamination reaction, D- or L-alanine, to the corresponding imine (see Figure 3e). The hereby produced H2O2 oxidizes, catalyzed by horse radish peroxidase, the dye pyrogallol red. The reaction can be monitored by measuring the decrease in absorbance around 540 nm. This method allows the use of many different amine donors as well as the determination of the enantiopreference of the transaminase. When using a β-amino acid instead of an amine, false positive results might occur if the amino acid oxidase (AAO) also oxidizes the educt and not only the coproduct. However, to our knowledge such AAO activity towards β-amino acids has never been reported. Further drawbacks include that free amino acids distort the results, which makes enzyme purification necessary and that as it is a multi-enzymatic reaction system, reaction conditions can only be changed marginally.
Conclusions and future areas of research
TAs possess a great potential for the enzymatic synthesis of enantiopure β-amino acids as these enzymes offer the possibility to gain a 100% yield in contrast to the conventional kinetic resolutions using other biocatalysts (see introduction). Transaminases are commonly used tools in the synthesis of various chemicals and pharmaceuticals. Thus production and purification of these enzymes in bulk quantities is well-established, and so is immobilization. Additionally, several process parameters for biotechnological applications are well investigated for both kinetic resolutions and asymmetric syntheses, e.g. the usage of different (co-)solvents and variation of pH and PLP concentration as well as different strategies of product removal (Koszelewski et al. 2008). Of special importance are the thoroughly tried and tested methods to shift the equilibrium to the product side by removal of the coproduct (kinetic resolutions) or degradation of the coproduct/recycling of the amino donor by different enzymes in asymmetric synthesis (Koszelewski et al. 2010).
All these benefits for technical applications are not established with aminomutases and only in part with hydantoinases (as described above), so TAs appear as the most promising candidates among the potential biocatalysts for a 100% yield synthesis of β-amino acids.
A key step in fulfilling this potential is the discovery of new TAs with a broader substrate spectrum and different enantioselectivity. This will be greatly facilitated by the HTP-activity assays described in this article, which allow for time and cost efficient screening, characterization and enzyme optimization. As has been discussed, transaminases which act on aliphatic β-amino acids are abundant, while only a small number of transaminases which act on aromatic β-amino acids have been described. The application of protein engineering to enhance the activity of TAs towards aromatic β-amino acids has been only moderately successful. The crystal structure of the transaminase of Mesorhizobium sp. LUK will lead to a more targeted approach in protein engineering.
Little attention so far has been paid to the preparation of the thermodynamically instable β-keto substrate. A possible route is the enzymatic hydrolysis of the corresponding β-keto-ester. Although such a route has already been described (Banerjee et al. 2005Kim et al. 2007) further optimization will be necessary for the development of efficient processes as the reported yields are quite low (~20%). This might be due to the loss of the intermediary β-keto acid via decarboxylation to acetophenone (which is not discussed in Kim et al. 2007).
This instability of the potential substrates indeed appears as the bottleneck in β-amino acid synthesis via transaminases. A more elegant solution could be obtained by changing the sequence in this coupled enzyme reaction: If the TA accepts the stable β-keto ester (1) the intermediary synthesis of the β-keto acid can be circumvented and (2) the adjacent application of an enantioselective lipase to subsequently cleave the intermediary chiral β-amino acid ester would further enhance the ee value. As the authors assume this can not happen in the reported reaction due to a mandatory anchoring of the substrate's carboxylic group by one of the two binding pockets around the PLP-lysine Schiff base (the external aldimine intermediate) which is certainly not possible with the esterified substrate (Kim et al. 2007).
However, advances in protein design and substrate modeling might help to overcome this problem, as for example the excavation of the small pocket of the commonly used transaminase ATA-117 allowed the (R)-selective amination of prositagliptin ketone to the antidiabetic compound sitagliptin (Savile et al. 2010) which was not successful before using a variety of unmodified TAs due to sterical hindrance.
Not least, the potential of TAs for the asymmetric synthesis of β-amino acids can be assumed to be even much higher, as most of the numerous commercially available TAs have never been tested with β-amino acids or β-keto acids as substrates (the latter due to their instability mentioned above). So the conclusive key step will be a modification of the HTP-assays described to allow a fast and comprehensive screening for β-TA activity.
We would like to thank the "Bundesministerium für Bildung und Forschung" (BMBF) for the financial support of this work within the joint project ''BioSysPro'': New enzymes and processes for biobased products via the integration of biotechnological and chemical methods.
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