Recent progress in directed evolution of stereoselective monoamine oxidases

Abstract

Monoamine oxidases (MAOs) use molecular dioxygen as oxidant to catalyze the oxidation of amines to imines. This type of enzyme can be employed for the synthesis of primary, secondary, and tertiary amines by an appropriate deracemization protocol. Consequently, MAOs are an attractive class of enzymes in biocatalysis. However, they also have limitations in enzyme-catalyzed processes due to the often-observed narrow substrate scope, low activity, or poor/wrong stereoselectivity. Therefore, directed evolution was introduced to eliminate these obstacles, which is the subject of this review. The main focus is on recent efforts concerning the directed evolution of four MAOs: monoamine oxidase (MAO-N), cyclohexylamine oxidase (CHAO), D-amino acid oxidase (pkDAO), and 6-hydroxy-D-nicotine oxidase (6-HDNO).

Keywords

Monoamine oxidase / Directed evolution / Stereoselectivity / Chiral amine

References

[1] Acevedo-Rocha CG, Agudo R, Reetz MT. Directed evolution of stereoselective enzymes based on genetic selection as opposed to screening systems. J Biotechnol, 2014, 191: 3-10.

[2] Acevedo-Rocha CG, Gamble CG, Lonsdale R, Li A, Nett N, Hoebenreich S, Lingnau JB, Wirtz C, Fares C, Hinrichs H. P450-catalyzed regio-and diastereoselective steroid hydroxylation: efficient directed evolution enabled by mutability landscaping. ACS Catal, 2018, 8(4): 3395-3410.

[3] Alexeeva M, Enright A, Dawson MJ, Mahmoudian M, Turner NJ. Deracemization of αα-methylbenzylamine using an enzyme obtained by in vitro evolution. Angew Chem Int Ed, 2002, 41(17): 3177-3180.

[4] Allen AE, MacMillan DW. Synergistic catalysis: a powerful synthetic strategy for new reaction development. Chem Sci, 2012, 3(3): 633-658.

[5] Arnold FH. Directed evolution: bringing new chemistry to life. Angew Chem Int Ed, 2018, 57(16): 4143-4148.

[6] Atodiresei I, Vila C, Rueping M. Asymmetric organocatalysis in continuous flow: opportunities for impacting industrial catalysis. ACS Catal, 2015, 5(3): 1972-1985.

[7] Bálint J, Egri G, Czugler M, Schindler J, Kiss V, Juvancz Z, Fogassy E. Resolution of α-phenylethylamine by its acidic derivatives. Tetrahedron Asymmetry, 2001, 12(10): 1511-1518.

[8] Blacker J, Headley CE. Dunn PJ, Wells A, Williams MT. Dynamic resolution of chiral amine pharmaceuticals: turning waste isomers into useful product. Green chemistry in the pharmaceutical industry, 2010, Weinheim: Wiley, 269-288.

[9] Blaser HU, Schmidt E. Asymmetric catalysis on industrial scale, 2004, Hoboken: Wiley.

[10] Bommarius AS, Blum JK, Abrahamson MJ. Status of protein engineering for biocatalysts: how to design an industrially useful biocatalyst. Curr Opin Chem Biol, 2011, 15(2): 194-200.

[11] Bornscheuer U, Huisman G, Kazlauskas RJ, Lutz S, Moore J, Robins K. Engineering the third wave of biocatalysis. Nature, 2012, 485(7397): 185-194.

[12] Brustad EM, Arnold FH. Optimizing non-natural protein function with directed evolution. Curr Opin Chem Biol, 2011, 15(2): 201-210.

[13] Cadwell RC, Joyce GF. Mutagenic PCR. PCR Methods Appl, 1994, 3(6): S136-S140.

[14] Carr R, Alexeeva M, Enright A, Eve TS, Dawson MJ, Turner NJ. Directed evolution of an amine oxidase possessing both broad substrate specificity and high enantioselectivity. Angew Chem Int Ed, 2003, 42(39): 4807-4810.

[15] Carr R, Alexeeva M, Dawson MJ, Gotor-Fernández V, Humphrey CE, Turner NJ. Directed evolution of an amine oxidase for the preparative deracemisation of cyclic secondary amines. ChemBioChem, 2005, 6(4): 637-639.

[16] Chen K, Arnold FH. Tuning the activity of an enzyme for unusual environments: sequential random mutagenesis of subtilisin E for catalysis in dimethylformamide. Proc Natl Acad Sci USA, 1993, 90(12): 5618-5622.

[17] Chen K, Huang X, Kan SJ, Zhang RK, Arnold FH. Enzymatic construction of highly strained carbocycles. Science, 2018, 360(6384): 71-75.

[18] Chen K, Zhang S-Q, Brandenberg OF, Hong X, Arnold FH. Alternate heme ligation steers activity and selectivity in engineered cytochrome P450-catalyzed carbene-transfer reactions. J Am Chem Soc, 2018, 140(48): 16402-16407.

[19] Choi J-M, Han S-S, Kim H-S. Industrial applications of enzyme biocatalysis: current status and future aspects. Biotechnol Adv, 2015, 33(7): 1443-1454.

[20] Clouthier CM, Kayser MM, Reetz MT. Designing new Baeyer-Villiger monooxygenases using restricted CASTing. J Org Chem, 2006, 71(22): 8431-8437.

[21] de Vries JG, Mršić N. Organocatalytic asymmetric transfer hydrogenation of imines. Catal Sci Technol, 2011, 1(5): 727-735.

[22] Denard CA, Ren H, Zhao H. Improving and repurposing biocatalysts via directed evolution. Curr Opin Chem Biol, 2015, 25: 55-64.

[23] Drauz K, Gröger H, May O. Enzyme catalysis in organic synthesis, 2012, Hoboken: Wiley

[24] Dunsmore CJ, Carr R, Fleming T, Turner NJ. A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines. J Am Chem Soc, 2006, 128(7): 2224-2225.

[25] Echeverria P-G, Ayad T, Phansavath P, Ratovelomanana-Vidal V. Recent developments in asymmetric hydrogenation and transfer hydrogenation of ketones and imines through dynamic kinetic resolution. Synthesis, 2016, 48(16): 2523-2539.

[26] Estell DA, Graycar TP, Wells JA. Engineering an enzyme by site-directed mutagenesis to be resistant to chemical oxidation. J Biol Chem, 1985, 260(11): 6518-6521.

[27] Gand M, Müller H, Wardenga R, Höhne M. Characterization of three novel enzymes with imine reductase activity. J Mol Catal B Enzym, 2014, 110: 126-132.

[28] Ghattas G, Chen D, Pan F, Klankermayer J. Asymmetric hydrogenation of imines with a recyclable chiral frustrated Lewis pair catalyst. Dalton Trans, 2012, 41(30): 9026-9028.

[29] Ghislieri D, Green AP, Pontini M, Willies SC, Rowles I, Frank A, Grogan G, Turner NJ. Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products. J Am Chem Soc, 2013, 135(29): 10863-10869.

[30] Gotor V, Alfonso I, García-Urdiales E. Asymmetric organic synthesis with enzymes, 2008, Hoboken: Wiley

[31] Guranda DT, van Langen LM, van Rantwijk F, Sheldon RA, Švedas VK. Highly efficient and enantioselective enzymatic acylation of amines in aqueous medium. Tetrahedron Asymmetry, 2001, 12(11): 1645-1650.

[32] Gustafson KP, Lihammar R, Verho O, Engstrom K, Bäckvall J-E. Chemoenzymatic dynamic kinetic resolution of primary amines using a recyclable palladium nanoparticle catalyst together with lipases. J Org Chem, 2014, 79(9): 3747-3751.

[33] Harvey AL. Natural products in drug discovery. Drug Discov Today, 2008, 13(19–20): 894-901.

[34] Heath RS, Pontini M, Bechi B, Turner NJ. Development of an R-selective amine oxidase with broad substrate specificity and high enantioselectivity. ChemCatChem, 2014, 6(4): 996-1002.

[35] Heath RS, Pontini M, Hussain S, Turner NJ. Combined imine reductase and amine oxidase catalyzed deracemization of nitrogen heterocycles. ChemCatChem, 2016, 8(1): 117-120.

[36] Hermanns N, Dahmen S, Bolm C, Bräse S. Asymmetric, catalytic phenyl transfer to imines: highly enantioselective synthesis of diarylmethylamines. Angew Chem Int Ed, 2002, 41(19): 3692-3694.

[37] Kirsch RD, Joly E. An improved PCR-mutagenesis strategy for two-site mutagenesis or sequence swapping between related genes. Nucleic Acids Res, 1998, 26(7): 681-683.

[38] Köhler V, Bailey KR, Znabet A, Raftery J, Helliwell M, Turner NJ. Enantioselective biocatalytic oxidative desymmetrization of substituted pyrrolidines. Angew Chem Int Ed, 2010, 49(12): 2182-2184.

[39] Lautens M, Larin EM. Pd/Zn-catalyzed asymmetric transfer hydrogenation of imines with alcohols. Synfacts, 2018, 14(07): 0730.

[40] Lee S. Designing enzymatic resolution of amines. Chem Commun, 1999, 2: 127-128.

[41] Leipold F, Hussain S, Ghislieri D, Turner NJ. Asymmetric reduction of cyclic imines catalyzed by a whole-cell biocatalyst containing an (S)-imine reductase. ChemCatChem, 2013, 5(12): 3505-3508.

[42] Leisch H, Grosse S, Iwaki H, Hasegawa Y, Lau PC. Cyclohexylamine oxidase as a useful biocatalyst for the kinetic resolution and dereacemization of amines. Can J Chem, 2011, 90(1): 39-45.

[43] Leung DW. A method for random mutagenesis of a defined DNA segment using a modified polymerase chain reaction. Technique, 1989, 1: 11-15.

[44] Li T, Liang J, Ambrogelly A, Brennan T, Gloor G, Huisman G, Lalonde J, Lekhal A, Mijts B, Muley S. Efficient, chemoenzymatic process for manufacture of the Boceprevir bicyclic [3.1. 0] proline intermediate based on amine oxidase-catalyzed desymmetrization. J Am Chem Soc, 2012, 134(14): 6467-6472.

[45] Li G, Ren J, Iwaki H, Zhang D, Hasegawa Y, Wu Q, Feng J, Lau PC, Zhu D. Substrate profiling of cyclohexylamine oxidase and its mutants reveals new biocatalytic potential in deracemization of racemic amines. Appl Microbiol Biotechnol, 2014, 98(4): 1681-1689.

[46] Li G, Ren J, Yao P, Duan Y, Zhang H, Wu Q, Feng J, Lau PC, Zhu D. Deracemization of 2-methyl-1,2,3,4-tetrahydroquinoline using mutant cyclohexylamine oxidase obtained by iterative saturation mutagenesis. ACS Catal, 2014, 4(3): 903-908.

[47] Li S, Li G, Meng W, Du H. A frustrated Lewis pair catalyzed asymmetric transfer hydrogenation of imines using ammonia borane. J Am Chem Soc, 2016, 138(39): 12956-12962.

[48] Li G, Yao P, Gong R, Li J, Liu P, Lonsdale R, Wu Q, Lin J, Zhu D, Reetz MT. Simultaneous engineering of an enzyme’s entrance tunnel and active site: the case of monoamine oxidase MAO-N. Chem Sci, 2017, 8(5): 4093-4099.

[49] Li G, Garcia-Borràs M, Fürst MJ, Ilie A, Fraaije MW, Houk KN, Reetz MT. Overriding traditional electronic effects in biocatalytic Baeyer–Villiger reactions by directed evolution. J Am Chem Soc, 2018, 140(33): 10464-10472.

[50] Li G, Wang J-b, Reetz MT. Biocatalysts for the pharmaceutical industry created by structure-guided directed evolution of stereoselective enzymes. Biorg Med Chem, 2018, 26(7): 1241-1251.

[51] Li G, Dong Y, Reetz MT. Can machine learning revolutionize directed evolution of selective enzymes?. Adv Synth Catal, 2019, 361(11): 2377-2386.

[52] List B. Emil Knoevenagel and the roots of aminocatalysis. Angew Chem Int Ed, 2010, 49(10): 1730-1734.

[53] Liu Y, Du H. Chiral dienes as “ligands” for borane-catalyzed metal-free asymmetric hydrogenation of imines. J Am Chem Soc, 2013, 135(18): 6810-6813.

[54] MacMillan DW. The advent and development of organocatalysis. Nature, 2008, 455(7211): 304-308.

[55] Mangas-Sanchez J, France SP, Montgomery SL, Aleku GA, Man H, Sharma M, Ramsden JI, Grogan G, Turner NJ. Imine reductases (IREDs). Curr Opin Chem Biol, 2017, 37: 19-25.

[56] Mitsukura K, Suzuki M, Tada K, Yoshida T, Nagasawa T. Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase. Org Biomol Chem, 2010, 8(20): 4533-4535.

[57] Mitsukura K, Kuramoto T, Yoshida T, Kimoto N, Yamamoto H, Nagasawa T. A NADPH-dependent (S)-imine reductase (SIR) from Streptomyces sp. GF3546 for asymmetric synthesis of optically active amines: purification, characterization, gene cloning, and expression. Appl Microbiol Biotechnol, 2013, 97(18): 8079-8086.

[58] Nguyen TB, Wang Q, Guéritte F. Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of ortho-hydroxybenzophenone N–H ketimines and applications. Chem Eur J, 2011, 17(35): 9576-9580.

[59] Ni Y, Holtmann D, Hollmann F. How green is biocatalysis? To calculate is to know. ChemCatChem, 2014, 6(4): 930-943.

[60] Noyori R. Asymmetric catalysis: science and opportunities (Nobel lecture). Angew Chem Int Ed, 2002, 41(12): 2008-2022.

[61] Oláh M, Boros Z, Hornyánszky G, Poppe L. Isopropyl 2-ethoxyacetate—an efficient acylating agent for lipase-catalyzed kinetic resolution of amines in batch and continuous-flow modes. Tetrahedron, 2016, 72(46): 7249-7255.

[62] Otten LG, Hollmann F, Arends IW. Enzyme engineering for enantioselectivity: from trial-and-error to rational design?. Trends Biotechnol, 2010, 28(1): 46-54.

[63] Porter JL, Rusli RA, Ollis DL. Directed evolution of enzymes for industrial biocatalysis. ChemBioChem, 2016, 17(3): 197-203.

[64] Poulhès F, Vanthuyne N, MlP Bertrand, Sp Gastaldi, Gr Gil. Chemoenzymatic dynamic kinetic resolution of primary amines catalyzed by CAL-B at 38–40 °C. J Org Chem, 2011, 76(17): 7281-7286.

[65] Quin MB, Schmidt-Dannert C. Engineering of biocatalysts: from evolution to creation. ACS Catal, 2011, 1(9): 1017-1021.

[66] Reetz MT. Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions. Angew Chem Int Ed, 2011, 50(1): 138-174.

[67] Reetz MT. Directed evolution of selective enzymes: catalysts for organic chemistry and biotechnology, 2016, Hoboken: Wiley

[68] Reetz MT. What are the limitations of enzymes in synthetic organic chemistry?. The Chemical Record, 2016, 16(6): 2449-2459.

[69] Reetz MT, Carballeira JD. Iterative saturation mutagenesis (ISM) for rapid directed evolution of functional enzymes. Nat Protoc, 2007, 2(4): 891-903.

[70] Reetz MT, Zonta A, Schimossek K, Jaeger KE, Liebeton K. Creation of enantioselective biocatalysts for organic chemistry by in vitro evolution. Angew Chem Int Ed Engl, 1997, 36(24): 2830-2832.

[71] Reetz MT, Bocola M, Carballeira JD, Zha D, Vogel A. Expanding the range of substrate acceptance of enzymes: combinatorial active-site saturation test. Angew Chem Int Ed, 2005, 44(27): 4192-4196.

[72] Reetz MT, Carballeira JD, Peyralans J, Höbenreich H, Maichele A, Vogel A. Expanding the substrate scope of enzymes: combining mutations obtained by CASTing. Chem Eur J, 2006, 12(23): 6031-6038.

[73] Reetz MT, Carballeira JD, Vogel A. Iterative saturation mutagenesis on the basis of B factors as a strategy for increasing protein thermostability. Angew Chem Int Ed, 2006, 45(46): 7745-7751.

[74] Reymond J-L. Enzyme assays: high-throughput screening, genetic selection and fingerprinting, 2006, Hoboken: Wiley.

[75] Rowles I, Malone KJ, Etchells LL, Willies SC, Turner NJ. Directed evolution of the enzyme monoamine oxidase (MAO-N): highly efficient chemo-enzymatic deracemisation of the Alkaloid (±)-crispine A. ChemCatChem, 2012, 4(9): 1259-1261.

[76] Sharpless KB. Searching for new reactivity (Nobel lecture). Angew Chem Int Ed, 2002, 41(12): 2024-2032.

[77] Sheldon RA, Pereira PC. Biocatalysis engineering: the big picture. Chem Soc Rev, 2017, 46(10): 2678-2691.

[78] Siedlecka R. Recent developments in optical resolution. Tetrahedron, 2013, 69(31): 6331-6363.

[79] Siloto RM, Weselake RJ. Site saturation mutagenesis: methods and applications in protein engineering. Biocatal Agric Biotechnol, 2012, 1(3): 181-189.

[80] Skalden L, Peters C, Ratz L, Bornscheuer UT. Synthesis of (1R,3R)-1-amino-3-methylcyclohexane by an enzyme cascade reaction. Tetrahedron, 2016, 72(46): 7207-7211.

[81] Stemmer WP. Rapid evolution of a protein in vitro by DNA shuffling. Nature, 1994, 370(6488): 389-391.

[82] Tao JA, Lin G-Q, Liese A. Biocatalysis for the pharmaceutical industry: discovery, development, and manufacturing, 2009, Hoboken: Wiley

[83] Thalén LK, Zhao D, Sortais JB, Paetzold J, Hoben C, Baeckvall JE. A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution: application to the synthesis of norsertraline. Chem Eur J, 2009, 15(14): 3403-3410.

[84] Turner NJ. Enantioselective oxidation of C-O and C–N bonds using oxidases. Chem Rev, 2011, 111(7): 4073-4087.

[85] Turner Nicholas J., Truppo Matthew D.. Biocatalytic Routes to Nonracemic Chiral Amines. Chiral Amine Synthesis, 2010, Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 431-459.

[86] Van Langen L, Oosthoek N, Guranda D, Van Rantwijk F, Švedas V, Sheldon R. Penicillin acylase-catalyzed resolution of amines in aqueous organic solvents. Tetrahedron Asymmetry, 2000, 11(22): 4593-4600.

[87] Vandeyar MA, Weiner MP, Hutton CJ, Batt CA. A simple and rapid method for the selection of oligodeoxynucleotide-directed mutants. Gene, 1988, 65(1): 129-133.

[88] Verho O, Bäckvall J-E. Chemoenzymatic dynamic kinetic resolution: a powerful tool for the preparation of enantiomerically pure alcohols and amines. J Am Chem Soc, 2015, 137(12): 3996-4009.

[89] Vetica F, Chauhan P, Dochain S, Enders D. Asymmetric organocatalytic methods for the synthesis of tetrahydropyrans and their application in total synthesis. Chem Soc Rev, 2017, 46(6): 1661-1674.

[90] Walsh PJ, Kozlowski MC. Fundamentals of asymmetric catalysis, 2009, Sausalito: University Science Books.

[91] Wang Y-B, Tan B. Construction of axially chiral compounds via asymmetric organocatalysis. Acc Chem Res, 2018, 51(2): 534-547.

[92] Yao P, Cong P, Gong R, Li J, Li G, Ren J, Feng J, Lin J, Lau PC, Wu Q. Biocatalytic route to chiral 2-substituted-1,2,3,4-tetrahydroquinolines using cyclohexylamine oxidase muteins. ACS Catal, 2018, 8(3): 1648-1652.

[93] Yasukawa K, Nakano S, Asano Y. Tailoring d-amino acid oxidase from the pig kidney to R-stereoselective amine oxidase and its use in the deracemization of αα-Methylbenzylamine. Angew Chem Int Ed, 2014, 53(17): 4428-4431.

[94] Yasukawa K, Motojima F, Ono A, Asano Y. Expansion of the substrate specificity of porcine kidney d-amino acid oxidase for S-stereoselective oxidation of 4-Cl-benzhydrylamine. ChemCatChem, 2018, 10(16): 3500-3505.

[95] Zeymer C, Hilvert D. Directed evolution of protein catalysts. Annu Rev Biochem, 2018, 87: 131-157.

[96] Zhang RK, Chen K, Huang X, Wohlschlager L, Renata H, Arnold FH. Enzymatic assembly of carbon-carbon bonds via iron-catalysed sp³ C-H functionalization. Nature, 2019, 565(7737): 67-72.

[97] Zhang RK, Huang X, Arnold FH. Selective C-H bond functionalization with engineered heme proteins: new tools to generate complexity. Curr Opin Chem Biol, 2019, 49: 67-75.

[98] Zheng L, Baumann U, Reymond J-L. An efficient one-step site-directed and site-saturation mutagenesis protocol. Nucleic Acids Res, 2004, 32(14): e115-e115.

[99] Zhou Q-L. Privileged chiral ligands and catalysts, 2011, Hoboken: Wiley

Funding

Young Scientists Fund(21807111)