Bioreductive preparation of ACE inhibitors precursor (R)-2-hydroxy-4-phenylbutanoate esters: Recent advances and future perspectives
© Xu and Ni; licensee Springer. 2015
Received: 12 November 2014
Accepted: 16 February 2015
Published: 31 March 2015
Optically active (R)-2-hydroxy-4-phenylbutanoate esters ((R)-HPBE) are key precursors for the production of angiotension-converting enzyme (ACE) inhibitors, which are important prescriptive drugs for preventing the formation of angiotensin II and lowering the blood pressure. The biocatalytic asymmetric reduction of ethyl 2-oxo-4-phenylbutanoate (OPBE) to (R)-HPBE with carbonyl reductases has several advantageous attributes, including high enantioselectivity, mild reaction condition, high catalytic efficiency, and environmental benignity. An increasing number of OPBE reductases have been discovered owing to the drastic achievements in genomics, screening and evolution technologies, and process engineering. The potential of (R)-HPBE production process has also been intensively evaluated. This review covers recent progress on the bioreductive preparation of (R)-HPBE, especially on various screening approaches for the identification of OPBE reductases and their characterization.
Optically active secondary alcohols, especially hydroxyl acids or hydroxyl acid esters, are important compounds for introducing chiral elements to pharmaceuticals, agricultural pesticides, and other fine chemicals [1-4]. (R)-2-hydroxy-4-phenylbutanoate esters (OPBE), one class of chiral alcohols, are important precursors for the production of serials of angiotensin-converting enzymes (ACE) inhibitors, generally named as pril drugs (benazepril, cilazapril, quinapril, and ramipril), possessing (S)-homophenylalanine moiety as pharmacophore [5-7]. ACE (Kininase II, peptidyldipeptide hydrolase, EC 184.108.40.206) could catalyze the production of vasoconstrictor angiotensin II and inactivation of vasodilator bradykinin. Whereas inhibitors of ACE could prevent the formation of angiotensin II, hence decrease the blood pressure [8,9]. Along with the economic development, the incidence of hypertension is higher and younger which may induce stroke, heart failure, heart attack, and kidney failure. The annual revenues of prescriptive antihypertensive drugs increased every year, with $45 billion in total at the end of 2011 . The ACE inhibitors drugs accounted for 10% among all the antihypertensive drugs. Hence, the preparation of their key chiral precursor (R)-HPBE is of special and increasingly interests.
Screening of microorganisms for bioreductive preparation of (R)-HPBE
Asymmetric reduction of OPBE into ( R )-HPBE employing microorganisms
Discovery and characterization of OPBE reductases
Although many wild-type microbial cells could catalyze the asymmetric reduction of OPBE into (R)-HPBE, their industrial applications are limited by a number of disadvantageous. The expression level and enzymatic properties of OPBE reductases are often undesirable in parent strains . Additionally, there might exist several enzymes with variable or opposite stereospecificity that could result HPBE with compromised chirality . And the fermentation conditions of wild-type strains are usually strict and time-consuming. Studies on the discovery and properties of isolated OPBE reductases are therefore of special interests to prompt the biocatalytic preparation of chiral (R)-HPBE.
Enzyme discovery strategies
Alongside the revolution of biotechnologies, a variety of tools are available for the quick screening and identification of biocatalysts. Several comprehensive reviews discussed the discovery and engineering tools developed to obtain naturally evolved or tailor-made enzymes with enhanced properties for chemical synthesis [29,30,40]. In the case of microbial strains isolated from natural environment, enzymes could be discovered through protein purification, insertional mutation, chromosome walking, shotgun library, etc. With regard to vast amount of genome information, genome hunting and genome database mining are two direct and time-saving strategies.
For a long time, purification of target enzymes from wild-type strains has been the dominant approach for enzyme discovery . Through several purification steps, such as ammonium sulfate precipitation, ion exchange chromatography, hydrophobic chromatography, affinity chromatography and gel chromatography, and pure or partially purified enzymes could be harvested. After characterization with protein NMR of terminal peptide and MS, the encoding gene sequence of target enzymes could be acquired. Various carbonyl reductases of different origins (microorganisms and plant tissues) have been discovered through microorganism isolation and protein purification. A robust carbonyl reductase was purified from Adzuki bean, with high enantioselectivity (>99% ee) and tolerance to α-chloroacetophenone (0.2 M) .
This strategy utilizes a proper transposon to insert randomly into the genome sequence and disturb the normal properties or phenotypes of the strains. Through screening for mutants exhibiting expected changes and sequencing, the target genes could be identified. Various novel enzymes and pathways have been discovered employing this method, such as two novel genes pao and sap from Pseudomonas sp. Strain HZN6, coding for 6-hydroxy-l-nicotine oxidase and NADP+-dependent 3-succinoylsemialdehyde-pyridine dehydrogenase in the catabolism of nicotine .
Based on conserved motif of certain enzymes, chromosome walking provided a new method to identify functional enzymes . A functional P450 monooxygenase from Rhodococcus sp. ECU0066 was identified by chromosome walking by several rounds of PCR, with capability in the enantioselective oxidation of sulfides .
Compared with other strategies, shotgun library was much more common and easier to operate in discover functional enzymes. Through construction the subclones of the genome in proper fragment length, a shotgun library could be developed. Many enzymes were identified using this approach. For example, Zhang and coworkers successfully cloned a novel arylamidase encoding gene from Paracoccus sp. strain FLN-7 which could hydrolyze amide pesticides .
In the case of available genome data, genome hunting could be adopted to identify the target enzymes by cloning all of the potential genes from this single genome. Through genome hunting, Ni and coworkers heterogeneously expressed 13 reductases genes from Bacillus sp. ECU0013. Among them, the FabG (a β-ketoacyl-ACP reductase) exhibited high efficiency in the asymmetric reduction of 620 g L−1 OPBE to (S)-HPBE, with no addition of external expensive cofactor and 99% ee. Although the product configuration is not the desired one, it could be converted to (R)-HPBE through one-step configuration inversion .
Genome database mining
Another effective and promising strategy for quick discovery of suitable enzymes is genome database mining for homologous protein sequences of targeted enzymes. Owing to the revolution of sequencing technology, there are 58,117 sequencing projects (including 6,649 complete projects, 23,552 permanent drafts, 26,572 incomplete projects, and 1,404 targeted projects) in genome online database as of September 2014, providing massive data on protein-coding genes . The selection of reported enzymes as probe and the choice of candidate proteins in database with moderate identity are the two key factors for the successful identification of new enzymes. The sequence of several known ethyl 4-chloro-3-oxobutanate (COBE) reductases was regarded as probes to search for novel enzymes in GenBank, resulting in an excellent reductase from Streptomyces coelicolor out of ten candidates for the synthesis of optically pure ethyl (S)-4-chloro-3-hydroxybutanoate, a chiral building blocks for HMG-CoA reductase inhibitors, with a stunning high productivity of 609 g L−1 day−1 .
Selected OPB(E) redutases
Enzymatic properties of oxidoreductases for producing ( R )-HPB derivatives
Specific activity [U mg −1 ]
K m [mM]
V max [U mg −1 ]
Opt. temp. [°C] b
Sub. loading [g L −1 ]
[g L −1 d −1 ] d
Paracoccus pantotrophus DSM 11072
Rhodococcus sp. ST-10
E. coli K12
Table 2 Enzymatic properties of oxidoreductases for producing (R)-HPBE from OPBE.
Classification of OPB(E) reductases
According to the amino acid sequence and metal-ion dependency, the carbonyl reductases could be divided into short-chain dehydrogenase/reductase (SDR), medium-chain dehydrogenase/reductase (MDR), long-chain dehydrogenase/reductase (LDR), and aldo-keto reductase (AKR) [61-63]. Key motif search in online databases (SDR, http://www.sdr-enzymes.org/; MDR, http://www.bioinfo.ifm.liu.se/services/mdr/; AKR, http://www.med.upenn.edu/akr/) reveals that PpADH belongs to SDR family, CgKR1, YOL151w, and PAR belong to MDR family, while Ypr1p, CgKR2, NcCR, and IolS are members of AKR. PAR is the only zinc-dependent carbonyl reductase. Tyr-Lys-Ser, Cys-His-Asp, and His-Tyr-Lys are common catalytic triads for SDR, MDR, and AKR, respectively [21,64,65]. Reductase YiaE from E. coli with reduction activity in the conversion of OPB into (R)-HPB was classified into 2-hydroxyacid dehydrogenase family (Table 2).
Regarding to crystal structure information of the OPBE reductases, protein crystal structure of IolS from Bacillus subtilis is the only one deposited in the PDB database (PDB accession no. 1PYF) . In the structure of IolS, the most common fold, (β/α)8 barrel motif, seems to form a barrel conformation. The cofactor (NAD(P)+/NAD(P)H) is bound at the C-terminal of internal β-barrel, extending in an extended conformation from the center of the barrel with no intra-molecular hydrogen bonds. Besides to the conserved folding, the catalytic tyrosine at 58 sites acts as an acid in the reduction reaction. The acidity is enhanced through a hydrogen bond with the lysine of catalytic triad, which also in turn forms a salt bridge with the aspartate. In the apo form, the hydrogen bond between catalytic Tyr58 and Lys84 was 3.25 Å. When NADP+ binds, the distance between the lysine ζ-amino group and the tyrosine hydroxyl is extended to 4.26 Å, which causes the disruption of this hydrogen bond due to a shift of Tyr58 towards the NADP+. Two additional amino acids Asp51 and Lys84, which complete the catalytic triad by activating the phenolic proton on the tyrosine, also present in IolS. The interactions between both residues in the holo conformation are mediated by hydrogen bonds with a water molecule.
Bioprocess engineering for improved efficiency
For a biocatalytic process, several parameters are critical to evaluate the efficiency, including space-time yield, total turnover number (TTN) of cofactor or reductase, productivity, etc. However, hydrophobic OPBE could cause the deactivation of enzymes and often requires longer reaction time to achieve a higher conversion rate . Consequently, the efficiency is usually at low level. Various process engineering strategies have been developed to solve the problems and improve the efficiency in the preparation of chiral secondary alcohols employing reductases.
Catalysts as well as cosubstrates should be commercially available or easily producible.
Product formation should be thermodynamically as well as kinetically favored and has no interference with the enzymes or with the subsequent isolation of desired product.
Regeneration should be practical and inexpensive and stable over a long period of time.
In the view of all these factors, the feasibility of glucose dehydrogenase, formate dehydrogenase, and isopropanol-coupled ketoreductase technologies have been proven. Formate dehydrogenase, however, exhibited low recycling efficiency on NADP+. Glucose dehydrogenase and isopropanol-coupled systems have been applied in the enantioselective synthesis of (R)-HPB derivatives. By using glucose dehydrogenases from B. subtilis, the TTN of NADP+ could reach as much as 32,039 in the asymmetric reduction of 330 g L−1 OPBE employing IolS from B. subtilis under assistance of 0.05 mM NADP+ (Figure 2A). PAR from Rhodococcus sp. ST-10 is a reductase with isopropanol oxidation activity. Itoh and coworkers adopted the substrate-coupled strategy in the preparation of (R)-HPBE with PAR (Figure 2B). Almost 195 g L−1 OPBE was completely reduced, and the TTN of NAD+ was 947. Isopropanol could not only work as cosubstrate, but also as cosolvent to increase the solubility of OPBE.
To realize a high substrate loading, substrate feeding at batches is an effective strategy to reduce the of substrate inhibition. A much higher catalytic efficiency could be achieved by substrate-feeding operation. In our studies using 1-L aqueous/octanol biphasic system, 30 g OPBE was fed once per hour for ten times (330 g in total). After 12 h of reaction, substrate conversion rate of >99% and space-time yield of 660 g L−1 day−1 were obtained at 330 g L−1 OPBE . The substrate loading was 1.6 times higher than that of the highest record reported so for. Additionally, a S/C ratio of 31.7 was attained, ranking the highest catalyst yield in the asymmetric reduction of OPBE, which was 0.02–4.12 as reported .
To alleviate the toxicity of hydrophobic OPBE/HPBE, interface bioreactors have been established. It is a biotransformation device between a hydrophilic carrier and a hydrophobic organic solvent as shown in Figure 4 . In this system, the biocatalyst was immobilized on the carrier surface between the hydrophilic and hydrophobic solvents. Interestingly, the recycling of cofactors could proceed smoothly, and the product separation was relatively easier than that for aqueous systems.
The smart control of OPBE concentration in the reaction medium could also be achieved by adsorbing the substrate on hydrophobic resins (Figure 4B). D’Arrigo and coworkers proved that XAD™ 1180, a polystyrenic adsorbent selected among several Amberlite resins, was effective in controlling the OPBE amount presented in water phase. OPBE (1 g L−1) could be reduced asymmetrically employing Pichia pastoris with 99% conversion and 95% ee (R) . Continuous batch reactor (CBR) was established combining the biotransformation and OPBE/HPBE adsorption. In the CBR unit, the bioreduction of OPBE was carried out for 48 h at a substrate-feeding flow rate of 1 mL min−1, resulting 95.1% ee (R) and conversion rate of 25%.
Biocatalytic preparation of chiral alcohol is gaining momentum. Due to its high enantioselectivity, bioreductive preparation of chiral (R)-HPBE has been regarded as one of the most promising approaches. There are enormous difference between natural environment (i. e., cytosolic conditions) and industrial environment. Free enzymes might face hash environment, such as molar scale reactants and increased hydrophobicity instead of millimolar reagents and physiological aqueous environment. To become an efficient tool in large-scale synthesis of (R)-HPBE, OPBE reductases should display the following properties: (1) ≥100 g L−1 substrate loading, (2) ≤5 g L−1 biocatalyst loading (≥20 substrate to catalyst ratio), (3) ≥98% conversion rate, (4) ≤24 h reaction time, and (5) ≥99% ee [21,28]. Although several biocatalytic reduction systems could reach high substrate loading, enantioselectivity, and conversion, the biocatalyst loadings are still at relatively high and the S/C ratio is relatively low, which would hinder the product separation procedure.
Biocatalytic stereoselective reduction for (R)-2-hydroxy-4-phenylbutanate esters is gaining momentum. Various OPBE reductaes have been identified and some of them have indicated promising potential for practical manufacture of (R)-HPBE. The discovery strategies for OPBE reductases and bioprocessing engineering strategies have been reviewed. Further development of bioreductive preparation of (R)-HPBE will require the continued mining and designing industrially useful enzymes and elaboration of process engineering.
We are grateful to the Natural Science Foundation of China (21276112), National Basic Research and Development Program of China (2011CB710800), and New Century Excellent Talents in University (NCET-11-0658) for the financial support of this research.
- Patel RN (2006) Biocatalysis: Synthesis of chiral intermediates for drugs. Curr Opin Drug Disc Dev 9:741–764Google Scholar
- Tao JH, Xu JH (2009) Biocatalysis in development of green pharmaceutical processes. Curr Opin Chem Biol 13:43–50View ArticleGoogle Scholar
- Magano J, Dunetz JR (2012) Large-scale carbonyl reductions in the pharmaceutical industry. Org Process Res Dev 16:1156–1184View ArticleGoogle Scholar
- Reetz MT (2013) Biocatalysis in organic chemistry and biotechnology: Past, Present, and Future. J Am Chem Soc 135:12480–12496View ArticleGoogle Scholar
- Iwasaki G, Kimura R, Numao N, Kondo K (1989) A practical and diastereoselective synthesis of angiotensin converting enzyme inhibitors. Chem Pharm Bull 37:280–283View ArticleGoogle Scholar
- Bradshaw CW, Wong CH, Hummel W, Kula MR (1991) Enzyme-catalyzed asymmetric synthesis of (S)-amino-4-phenylbutanoic acid and (R)-2-hydroxy-4-phenylbutanoic acid. Bioorg Chem 19:29–39View ArticleGoogle Scholar
- D’Arrigo P, Pedrocchi-Fantoni G, Servi S (2010) Chemo-enzymatic synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate. Tetrahedron Asymmetry 21:914–918View ArticleGoogle Scholar
- Parmley WW (1998) Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am J Med 105:27S–31SView ArticleGoogle Scholar
- Maruyama S, Nakagomi K, Tomizuka N, Suzuki H (1985) Angiotensin I-converting enzyme inhibitor derived from an enzymatic hydrolysate of casein. II. Isolation and bradykinin-potentiating activity on the ileum of rats. Agric Biol Chem 49:1405–1409View ArticleGoogle Scholar
- Crandall MA (2007) The world cardiovascular drug market, 2nd edition, Kalorama Information, SKU:KLI1397872.Google Scholar
- Baskar B, Pandian NG, Priya K, Chadha A (2004) Asymmetric reduction of alkyl 2-oxo-4-arylbutanoates and –but-3-enoates by Candida parapsilosis ATCC 7330: assignment of the absolute configuration of ethyl 2-hydeoxy-4-(p-methylphenyl)but-3-enoate by 1H NMR. Tetrahedron Asymmetry 15:3961–3966View ArticleGoogle Scholar
- Huang SH, Tsai SW (2004) Kinetic resolution of (R, S)-ethyl 2-hydeoxyl-4-phenylbutyrate via lipase-catalyzed hydrolysis and transesterification in isooctane. J Mol Catal B: Enzyme 28:65–69View ArticleGoogle Scholar
- Zhu LF, Meng QH, Fan WZ, Xie XM, Zhang ZG (2010) Direct asymmetric hydrogenation of 2-oxo-4-arylbut-3-enoic acids. J Org Chem 75:6027–6030View ArticleGoogle Scholar
- Aldea R, Alper H (1998) Hydrogenation of the carbonyl group in α-kektoesters and α-ketoamides catalyzed by ruthenium clay. J Org Chem 63:9425–9426View ArticleGoogle Scholar
- Rodrigues JAR, Milagre HMS, Milagre CDF, Moran PJS (2005) A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: Key intermediates of taxol side chain and phenylnorstatine. Tetrahedron Asymmetry 16:3099–3106View ArticleGoogle Scholar
- Meng QH, Zhu LF, Zhang ZG (2008) Highly enantioselective sequential hydrogenation of ethyl 2-oxo-4-arylbut-3-enoate to ethyl 2-hydroxy-4-arylbutyrate. J Org Chem 73:7209–7212View ArticleGoogle Scholar
- Zhang W, Ni Y, Sun ZH, Zheng P, Lin WQ, Zhu P, Ju NF (2009) Biocatalytic synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate with Candida krusei SW2-26: a practical process for high enantiopurity and product titer. Process Biochem 44:1270–1275View ArticleGoogle Scholar
- Noyori R (2003) Asymmetric catalysis: Science and opportunities. Adv Synth Catal 345:15–32View ArticleGoogle Scholar
- Noyori R, Yamakawa M, Hashiguchi S (2011) Metal-ligand bifuctional catalysis: a nonclassical mechanism for asymmetric hydrogen transfer between alcohols and carbonyl compounds. J Org Chem 66:7931–7944View ArticleGoogle Scholar
- Hall M, Bommarius AS (2011) Enantioenriched compounds via enzyme-catalyzed redox reactions. Chem Rev 111:4088–4110View ArticleGoogle Scholar
- Hollmann F, Arends IWCE, Holtmann D (2011) Enzymatic reductions for the chemist. Green Chem 13:2285–2314View ArticleGoogle Scholar
- Blaser HU, Jalett HP, Wiehl J (1991) Enantioselective hydrogenation of alpha-ketoesters with chinchona-modified platinum catalysts—Effect of acidic and basic solvents and additives. J Mol Catal 68:215–222View ArticleGoogle Scholar
- LeBlond C, Wang J, Liu J, Andrews AT, Sun YK (1999) Highly enantioselective heterogeneously catalyzed hydrogenation of α-ketoesters under mild conditions. J Am Chem Soc 121:4920–4921View ArticleGoogle Scholar
- Schoemaker HE, Mink D, Wubbolts MG (2003) Dispelling the myths—Biocatalysis in industrial synthesis. Science 299:1694–1697View ArticleGoogle Scholar
- Rollin JA, Tamb TK, Zhang PYH (2013) New biotechnology paradigm: Cell-free biosystems for biomanufacturing. Green Chem 15:1708–1719View ArticleGoogle Scholar
- Schmid A, Dordick JS, Hauer B, Kiener A, Wubbolts M, Witholt B (2001) Industrial biocatalysis today and tomorrow. Nature 409:258–268View ArticleGoogle Scholar
- Bai YL, Yang ST (2005) Biotransformation of (R)-2-hydeoxy-4-phenylbutyric acid be D-lactate dehydrogenase and Candida boidinii cells containing formate dehydrogenase coimmbolized in a fibrous bed bioreactor. Biotechnol Bioeng 92:137–146View ArticleGoogle Scholar
- Luetz S, Giver L, Lalonde J (2008) Engineered enzymes for chemical production. Biotechnol Bioeng 101:647–653View ArticleGoogle Scholar
- Behrens GA, Hummel A, Padhi SK, Schaetzle S, Bornscheuer UT (2011) Discovery and protein engineering of biocatalysts for organic synthesis. Adv Synth Catal 353:2191–2215View ArticleGoogle Scholar
- Bommarius AS, Blum JK, Abrahamson MJ (2011) Status of protein engineering for biocatalysts: how to design an industrially useful biocatalyst. Curr Opin Chem Biol 15:194–200View ArticleGoogle Scholar
- Bornscheuer UT, Huisman GW, Kazlauskas RJ, Lutz S, Moore JC, Robins K (2012) Engineering the third wave of biocatalysis. Nature 485:185–194View ArticleGoogle Scholar
- Davids T, Schmidt M, Boettcher D, Bornscheuer UT (2013) Strategies for the discovery and engineering of enzymes for biocatalysis. Curr Opin Chem Biol 17:215–220View ArticleGoogle Scholar
- Oda S, Ohta H (1992) Microbial transformation on interface between hydrophilic carriers and hydrophobic organic solvents. Biosci Biotechnol Biochem 56:2041–2045View ArticleGoogle Scholar
- Oda S, Inada Y, Kobayashi A, Ohta H (1998) Production of ethyl (R)-2-hydroxy-4-phenylbutanoate via reduction of ethyl 2-oxo-4-phenylbutanoate in an interface bioreactor. Biosci Biotechnol Biochem 62:1762–1767View ArticleGoogle Scholar
- de Lacerda PSB, Ribeiro JB, Leite SGF, Ferrara MA, Coelho RB, Bon EPS, da Silva Lima EL, Antunes OAC (2006) Microbial reduction of ethyl 2-oxo-4-phenylbutyrate. Searching for R-enantioselectivity. New access to the enalapril like ACE inhibitors. Tetrahedron Asymmetry 17:1186–1188View ArticleGoogle Scholar
- Chadha A, Manohar M, Soundararajan T, Lokeswari TS (1996) Asymmetric reduction of 2-oxo-4-phenylbutanoic acid ethyl ester by Daucus carota cell cultures. Tetrahedron Asymmetry 7:1571–1572View ArticleGoogle Scholar
- Chen YZ, Lin H, Xu XY, Xia SW, Wang LX (2008) Preparation the key intermediate of angiotensin-converting enzyme (ACE) inhibitors: High enantioselective production of ethyl (R)-2-hydeoxy-4-phenylbutyrate with Candida boidinii CIOC21. Adv Synth Catal 350:426–430View ArticleGoogle Scholar
- He CM, Chang DL, Zhang J (2008) Asymmetric reduction of substituted α- and β-ketoesters by Bacillus pumilus Phe-C3. Tetrahedron Asymmetry 19:1347–1351View ArticleGoogle Scholar
- Dao DH, Okamura M, Akasaka T, Kawai Y, Hida K, Ohno A (1998) Stereochemical control in microbial reduction. Part 31: Reduction of alkyl 2-oxo-4-arylbutyrates by baker’s yeast under selected reaction conditions. Tetrahedron Asymmetry 9:2725–2737View ArticleGoogle Scholar
- Ni Y, Xu JH (2012) Biocatalytic ketone reduction: a green and efficient access to enantiopure alcohols. Biotechnol Adv 30:1279–1288View ArticleGoogle Scholar
- Nakamura K, Yamanaka R, Matsuda T, Harada T (2003) Recent developments in asymmetric reduction of ketones with biocatalysts. Tetrahedron Asymmetry 14:2659–2681View ArticleGoogle Scholar
- Xie Y, Xu JH, Lu WY, Lin GQ (2009) Adzuki bean: a new resource of biocatalyst for asymmetric reduction of aromatic ketones with high stereoselectivity and substrate tolerance. Bioresour Technol 100:2463–2468View ArticleGoogle Scholar
- Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (1989) Identification of cystic fibrosis gene: Chromosome walking and jumping. Science 245:1059–1065View ArticleGoogle Scholar
- Qiu JG, Yun M, Wen YZ, Chen LS, Wu LF, Liu WP (2012) Functional identification of two novel genes from Pseudomonas sp. strain HZN6 involved in the catabolism of nicotine. Appl Environ Microbiol 78:2154–2160View ArticleGoogle Scholar
- Zhang JD, Li AT, Yang Y, Xu JH (2010) Sequence analysis and heterologous expression of a new cytochrome P450 monooxygenase from Rhodococcus sp for asymmetric sulfoxidation. Appl Microbiol Biotechnol 85:615–624View ArticleGoogle Scholar
- Zhang J, Yin JG, Hang BJ, Cai S, He J, Zhou SG, Li SP (2012) Cloning of a novel arylamidase gene from Paracoccus sp. strain FLN-7 that hydrolyzes amide pesticides. Appl Environ Microbiol 78:4848–4855View ArticleGoogle Scholar
- Ni Y, Li CX, Zhang J, Shen ND, Bornscheuer UT, Xu JH (2011) Efficient reduction of ethyl 2-oxo-4-phenylbutyrate at 620 g/L by a bacterial reductase with broad substrate spectrum. Adv Synth Catal 353:1213–1217View ArticleGoogle Scholar
- Reddy TBK, Thomas AD, Stamatic D, Bertsch J, Isbandi M, Jansson J, Mallajosyula J, Pagani I, Lobos EA, Kyrpides NC (2014) The genomes online database (GOLD) v.5: a metadata management system based on a four level (meta)genome project classification. Nucl Acids Res doi: 10.1093/nar/gku950.
- Wang LJ, Li CX, Ni Y, Zhang J, Liu X, Xu JH (2011) Highly efficient synthesis of chiral alcohols with a novel NADH-dependent reductase from Streptomyces coelicolor. Bioresour Technol 102:7023–7028View ArticleGoogle Scholar
- Itoh N, Morihama R, Wang JC, Okada K, Mizuguchi N (1997) Purification and characterization of phenylacetaldeyde reductase from a styrene-assimilating Corynebacterium strain, ST-10. Appl Environ Microbiol 63:3783–3788Google Scholar
- Makino Y, Dairi T, Itoh N (2007) Engineering the phenylacetaldehyde reductase mutant for improved substrate conversion in the presence of concentrated 2-propanol. Appl Microbiol Biotechnol 77:833–843View ArticleGoogle Scholar
- Itoh N, Isotani K, Nakamura M, Inoue K, Isogai Y, Makino Y (2012) Efficient synthesis of optically pure alcohols by asymmetric hydrogen-transfer biocatalysis: application of engineered enzymes in a 2-propanol-water medium. Appl Microbiol Biotechnol 93:1075–1085View ArticleGoogle Scholar
- Lavandera I, Kern A, Schaffenberger M, Gross J, Glieder A, Glieder A, de Wildeman S, Kroutil W (2008) An exceptionally DMSO-tolerant alcohol dehydrogenase for the stereoselective reduction of ketones. ChemSusChem 1:431–436View ArticleGoogle Scholar
- Kaluzna IA, Andrew AA, Bonilla M, Martzen MR, Stewart JD (2002) Enantioselective reductions of ethyl 2-oxo-4-phenylbutyrate by Saccharomyces cerevisiae dehydrogenases. J Mol Catal B: Enzymatic 17:101–105View ArticleGoogle Scholar
- Kaluzna IA, Matsuda T, Sewell AK, Stewart JD (2004) Systematic investigation of Saccharomyces cerevisiae enzymes catalyzing carbonyl reductions. J Am Chem Soc 126:12827–12832View ArticleGoogle Scholar
- Richter N, Hummel W (2011) Biochemical characterization of a NADPH-dependent carbonyl reductase from Neurospora crassa reducing α- and β-keto esters. Enzyme Microbial Technol 48:472–479View ArticleGoogle Scholar
- Ni Y, Su YN, Li HD, Zhou JY, Sun ZH (2013) Scalable biocatalytic synthesis of optically pure ethyl (R)-2-hydroxy-4-phenylbutyrate using a recombinant E. coli with high catalyst yield. J Biotechnol 168:493–498View ArticleGoogle Scholar
- Ma HM, Yang LL, Ni Y, Zhang J, Li CX, Zheng GW, Yang HY, Xu JH (2012) Stereospecific reduction of methyl o-chlorobenzoylformate at 300 g · L−1 without additional cofactor using a carbonyl reductase mined from Candida glabrata. Adv Synth Catal 354:1764–1772Google Scholar
- Shen ND, Ni Y, Ma HM, Wang LJ, Li CX, Zheng GW, Zhang J, Xu JH (2012) Efficient synthesis of a chiral precursor for angiotensin-converting enzyme (ACE) inhibitors in high space-time yield by a new reductase without external cofactors. Org Lett 14:1982–1985View ArticleGoogle Scholar
- Yun HD, Choi HL, Fadnavis NW, Kim BG (2005) Stereosepecific synthesis of (R)-2-hydroxy carboxylic acids using recombinant E. coli BL21 overexpressing YiaE from Escherichia coli K12 and glucose dehydrogenase from Bacillus subtilis. Biotechnol Prog 21:366–371View ArticleGoogle Scholar
- Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jörnvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U (2009) The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chemico-Biol Interact 178:94–98View ArticleGoogle Scholar
- Hedlund J, Jörnvall H, Persson B (2010) Subdivision of the MDR superfamily of medium chain dehydrogenases/reductases through iterative hidden Markov model refinement. BMC Bioinformatics 11:534–549View ArticleGoogle Scholar
- Hyndman D, Bauman DR, Heredia VV, Penning M (2003) The aldo-keto reductase superfamily homepage. Chemico-Biol Interact 143–144:621–631View ArticleGoogle Scholar
- Hwang CC, Chang YH, Hsu CN, Hsu HH, Li CW, Pon HI (2005) Mechanistic roles of Ser-114, Tyr-155, and Lys-159 in 3-hydroxysteroid dehydrogenase/carbonyl reductase from Comamonas testosteroni. J Biol Chem 280:3522–3528View ArticleGoogle Scholar
- Ehrensberger AH, Wilson DK (2004) Structural and catalytic diversity in the two family 11 aldo-keto reductases. J Mol Biol 337:661–673View ArticleGoogle Scholar
- Robert X, Gouet P (2014) Deciphering key features in protein structures with the new ENDscript server. Nucl Acid Res 42:W320–W324View ArticleGoogle Scholar
- Moore JC, Pollard DJ, Kosjek B, Devine PN (2007) Advances in the enzymatic reduction of ketones. Acc Chem Res 40:1412–1419View ArticleGoogle Scholar
- Zhao HM, van der Donk WA (2003) Regeneration of cofactors for use in biocatalysis. Curr Opin Biotechnol 14:583–589View ArticleGoogle Scholar
- Huisman GW, Liang J, Krebber A (2010) Practical chiral alcohol manufacture using ketoreductases. Curr Opin Chem Biol 14:122–129View ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.