SpringerLink
Log in

Current state and perspectives of penicillin G acylase-based biocatalyses

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

In the course of more than 60-year history, penicillin G acylase (PGA) gained a unique position among enzymes used by pharmaceutical industry for production of β-lactam antibiotics. Kinetically controlled enzymatic syntheses of cephalosporins of novel generations in which PGA catalyzes coupling of activated acyl donor with nucleophile belong among the latest large-scale applications. Contrary to rather specific roles of other enzymes involved in β-lactam biocatalyses, the PGA seems to have the greatest potential. On the laboratory scale, other applications with industrial potential were described, e.g., directed evolution of the enzyme to meet specific demands of industrial processes or its modification into the enzyme catalyzing reactions with novel substrates. The fact that β-lactams represent the most important group of antibiotics comprising 65 % of the world antibiotic market explains such a tremendous and continuous interest in this enzyme. Indeed, the annual consumption of PGA has recently been estimated to range from 10 to 30 million tons. The application potential of the enzyme goes beyond the β-lactam biocatalysis due to its enantioselectivity and promiscuity: the PGA can be used for the production of achiral and chiral compounds convenient for the preparation of synthons and active pharmaceutical ingrediences, respectively. These biocatalyses, however, still wait for large-scale application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abian O, Mateo C, Fernandez-Lorente G, Guisan JM, Fernandez-Lafuente R (2004) Thermodynamically controlled synthesis of amide bonds catalyzed by highly organic solvent-resistant penicillin acylase derivatives. Biotechnol Prog 20:117–121

    PubMed  CAS  Google Scholar 

  • Aboul-Enein HY, Abou-Basha LI (1997) Chirality and drug hazards. In: Aboul-Enein HY, Wainer IW (eds) The impact of stereochemistry on drug development and use. Wiley, New York, pp 1–19

    Google Scholar 

  • Aguirre C, Conchaa I, Vergara J, Riveros R, Illanes A (2010) Partition and substrate concentration effect in the enzymatic synthesis of cephalexin in aqueous two-phase systems. Process Biochem 45(7):1163–1167

    CAS  Google Scholar 

  • Alkema WBL, Prins AK, de Vries E, Janssen DB (2002a) Role of αArg145 and βArg263 in the active site of penicillin acylase of Escherichia coli. Biochem J 365:303–309

    PubMed Central  PubMed  CAS  Google Scholar 

  • Alkema WBL, Dijkhuis AJ, de Vries E, Janssen DB (2002b) The role of hydrophobic active-site residues in substrate specificity and acyl transfer activity of penicillin acylase. Eur J Biochem 269:2093–2100

    PubMed  CAS  Google Scholar 

  • Alkema WBL, Hensgens CMH, Snijder HJ, Keizer E, Dijkstra BW, Janssen DB (2004) Structural and kinetic studies on ligand binding in wild-type and active-site mutants of penicillin acylase. Protein Eng Des Sel 17(5):473–480

    PubMed  CAS  Google Scholar 

  • Aramori I, Fugukawa M, Isogai T, Iwami M, Kojo H (1991) Cephalosporin C acylase. Patent EP 0 475 652 A2

  • Bahamondes C, Wilson L, Aguirre C, Illanes (2012) A comparative study of the enzymatic synthesis of cephalexin at high substrate concentration in aqueous and organic media using statistical model. Biotechnol Bioprocess Eng 4:11–721

    Google Scholar 

  • Bahman SM, Mohammad AS, Akbarzadeh A, Mona S, Gigloo SH, Ali F, Dariush N (2013) Characteristics of penicillin G acylase into iron oxide nanoparticles. Br Biotechnol J 3:367–376

    CAS  Google Scholar 

  • Barber MS, Giesecke U, Reichert A, Minas W (2004) Industrial enzymatic production of cephalosporin-based β-lactams. Adv Biochem Eng Biotechnol 88:175–215

    Google Scholar 

  • Barends TRM, Polderman-Tijmes JJ, Jekel PA, Hensgens CMH, de Vries EJ, Janssen DB, Dijkstra BW (2003) The sequence and crystal structure of the α-amino acid ester hydrolase from Xanthomonas citri define a new family of β-lactam antibiotic acylases. J Biol Chem 278:23076–23084

    PubMed  CAS  Google Scholar 

  • Barends TRM, Polderman-Tijmes JJ, Jekel PA, Williams C, Wybenga G, Janssen DB, Dijkstra BW (2006) Acetobacter turbidans α-amino acid ester hydrolase: how a single mutation improves an antibiotic-producing enzyme. J Biol Chem 281:5804–5810

    PubMed  CAS  Google Scholar 

  • Basso A, Braiuca P, De Martin L, Ebert C, Gardossi L, Linda P (2000) d-phenylglycine and d-4-hydroxyphenylglycine methyl esters via penicillin G acylase catalysed resolution in organic solvents. Tetrahedron Asymmetry 11:1789–1796

    CAS  Google Scholar 

  • Bečka S, Štěpánek V, Vyasarayani RW, Grulich M, Maršálek J, Plháčková K, Dobišová M, Marešová H, Plačková M, Valešová R, Palyzová A, Datla A, Ashar TK, Kyslík P (2013) Penicillin G acylase from Achromobacter sp. CCM 4824. Appl Microbiol Biotechnol. doi:10.1007/s00253-013-4945-3

  • Bergeron LM, Tokatlian T, Gomez L, Clark DS (2009) Redirecting the inactivation pathway of penicillin amidase and increasing amoxicillin production via a thermophilic molecular chaperone. Biotechnol Bioeng 102(2):417–424

    PubMed  CAS  Google Scholar 

  • Bernardino SM, Fernandes P, Fonseca LP (2009) A new biocatalyst: penicillin G acylase immobilized in sol–gel micro-particles with magnetic properties. Biotechnol J 4:695–702

    PubMed  CAS  Google Scholar 

  • Blinkovsky AM, Markaryan AN (1993) Synthesis of β-lactam antibiotics containing α-aminophenylacetyl group in the acyl moiety catalyzed by d(-)-phenylglycyl-β-lactamide amidohydrolase. Enzyme Microb Technol 15:965–973

    Google Scholar 

  • Blum JK, Bommarius AS (2010) Amino ester hydrolase from Xanthomonas campestris pv. campestris, ATTC 33913 for enzymatic synthesis of ampicillin. J Mol Catal B Enzym 67(1/2):21–28

    PubMed Central  PubMed  CAS  Google Scholar 

  • Blum JK, Deaguero AL, Perez CV, Bommarius AS (2010) Ampicillin synthesis using a two-enzyme cascade with both α-amino ester hydrolase and penicillin G acylase. ChemCat Chem 2:987–991

    CAS  Google Scholar 

  • Braiuca P, Ebert C, Fischer L, Gardossi L, Linda P (2003) A homology model of penicillin acylase from Alcaligenes faecalis and in silico evaluation of its selectivity. Chem Bio Chem 4:615–622

    PubMed  CAS  Google Scholar 

  • Braiuca P, Ebert C, Basso A, Linda P, Gardossi L (2006) Computational methods to rationalize experimental strategies in biocatalysis. Trends Biotechnol 24:419–425

    PubMed  CAS  Google Scholar 

  • Bruggink A, Roos EC, de Vroom E (1998) Penicillin acylase in the industrial production of β-lactam antibiotics. Org Process Res Dev 2:128–133

    CAS  Google Scholar 

  • Calleri E, Massolini G, Loiodice F, Fracchiolla G, Temnporino C, Félix G, Tortorella P, Caccialanza G (2002) Evaluation of a penicillin G acylase-based chiral stationary phase towards a series of 2-aryloxyalkanoic acids, isosteric analogs and 2-arylpropionic acids. J Chromatogr A 958:131–140

    PubMed  CAS  Google Scholar 

  • Carboni C, Quadflieg PJLM, Broxterman QB, Linda P, Gardossi L (2004) Quantitative enzymatic protection of d-amino acid methyl esters by exploiting “relaxed” enantioselectivity of penicillin-G amidase in organic solvent. Tetrahedron Lett 45:4649–4652

    Google Scholar 

  • Carboni C, Kierkel HGT, Gardossi L, Tamiola K, Janssen DB, Quadflieg PJLM (2006) Preparation of d-amino acid by enzymatic kinetic resolution using a mutant of penicillin-G acylase from E. coli. Tetrahedron Asymmetry 17:245–251

    CAS  Google Scholar 

  • Cecchini DA, Serra I, Ubiali D, Terreni M, Albertini AM (2007) New active site oriented glyoxyl-agarose derivatives of Escherichia coli penicillin G acylase. BMC Biotechnol 7:54

    PubMed Central  PubMed  Google Scholar 

  • Cecchini DA, Pavesi R, Sanna S, Daly S, Xaiz R, Pregnolato M, Terreni M (2012) Efficient biocatalyst for large-scale synthesis of cephalosporins, obtained by combining immobilization and site-directed mutagenesis of penicillin acylase. Appl Microbiol Biotechnol 95:1491–1500

    PubMed  CAS  Google Scholar 

  • Chandel AK, Rao LV, Narasu ML, Singh OV (2008) The realm of penicillin G acylase in ß-lactam antibiotics. Enzyme Microb Technol 42:199–207

    CAS  Google Scholar 

  • Chen R (2012) Bacterial expression system for recombinant protein production: E. coli and beyond. Biotechnol Adv 30:1102–1107

    PubMed  CAS  Google Scholar 

  • Cheng T, Chen M, Zheng H, Wang J, Yang S, Jiang W (2006) Expression and purification of penicillin G acylase enzymes from four different micro-organisms, and a comparative evaluation of their synthesis/hydrolysis ratios for cephalexin. Protein Expr Purif 46(1):107–113

    PubMed  CAS  Google Scholar 

  • Chilov GG, Moody HM, Boosten WHJ, Švedas VK (2003) Resolution of (RS)-phenylglycinonitrile by penicillin acylase-catalyzed acylation in aqueous medium. Tetrahedron Asymmetry 14:2613–2617

    CAS  Google Scholar 

  • Crawford L, Stepan AM, McAda PC, Rambosek JA, Conder MJ, Vinci VA, Reeves CD (1995) Production of cephalosporin intermediates by feeding adipic acid to recombinant Penicillium chrysogenum strains expressing ring expansion activity. Biotechnology (NY) 13:58–62

    CAS  Google Scholar 

  • Datta S, Christena LR, Rajaram YRS (2013) Enzyme immobilization: an overview on techniques and support materials. 3. Biotechnology 3:1–9

    Google Scholar 

  • Deaguero AL, Blum JK, Bommarius AS (2012) Improving the diastereoselectivity of penicillin G acylase for ampicillin synthesis from racemic substrates. Protein Eng Des Sel 25:135–144

    PubMed  CAS  Google Scholar 

  • Didžiapetris R, Drabnik B, Schellenberger V, Jakubke H-D, Švedas V (1991) Penicillin acylase-catalyzed protection and deprotection of amino groups as a promissing approach in enzymatic peptide synthesis. FEBS Lett 287:31–33

    PubMed  Google Scholar 

  • Du LL, Wu Q, Chen CX, Liu BK, Lin XF (2009) A two-step, one-pot enzymatic synthesis of ampicillin from penicillin G potassium salt. J Mol Catal B Enzym 58:208–211

    CAS  Google Scholar 

  • Duggleby HJ, Tolley SP, Hill CP, Dodson EJ, Dodson G, Moody PC (1995) Penicillin acylase has a single-amino-acid catalytic centre. Nature 373(6511):264–268

    PubMed  CAS  Google Scholar 

  • Erarslan A, Terzi I, Guray A, Bermek E (1991) Purification and kinetics of penicillin G acylase from a mutant strain of Escherichia coli ATCC 11105. J Chem Technol Biotechnol 51:27–40

    CAS  Google Scholar 

  • Estruch I, Tagliani AR, Guisán JM, Fernández-Lafuente R, Alcántara AR, Toma L, Terreni M (2008) Immobilization of the acylase from Escherichia coli on glyoxyl-agarose gives efficient catalyst for the synthesis of cephalosporins. Enzyme Microb Technol 42:121–129

    Google Scholar 

  • Fadnavis NW, Sharfuddin M, Vadivel SK, Bhalerao UT (1997) Efficient chemoenzymatic synthesis of (2S,3S)-3-hydroxyleucine mediated by immobilised penicilin G acylase. J Chem Soc Perkin Trans 1(24):3577–3578

    Google Scholar 

  • Fadnavis NW, Devi AV, Jasti LS (2008) Resolution of racemic 2-chlorophenyl glycine with immobilized penicillin G acylase. Tetrahedron Asymmetry 19:2363–2366

    CAS  Google Scholar 

  • Feng XF, Liang SH, Lou WY (2008) Two-step, one-pot enzymatic synthesis of cefprozil from -phenylacetamido-3-propenyl-cephalosporanic acid (GPRA). Biocatal Biotransform 26(4):321–326

    CAS  Google Scholar 

  • Fernandez-Lafuente R, Hernández-Jústiz O, Mateo C, Terrini M, Alonso J, Garcia-López JL, Moreno MA, Guisan JM (2001) Stabilization of a tetrameric enzyme (α-amino acid ester hydrolase from Acetobacter turbidans) enables a very improved performance of ampicillin synthesis. J Mol Catal B Enzym 11:633–638

    CAS  Google Scholar 

  • Forciniti D (2008) Industrial bioseparations: principles and practice. Blackwell, Ames

    Google Scholar 

  • Fritz-Wolf K, Koller KP, Lange G, Liesum A, Sauber K, Schreuder H, Aretz W, Kabsch W (2002) Structure-based prediction of modifications in glutarylamidase to allow single-step enzymatic production of 7-aminocephalosporanic acid from cephalosporin C. Protein Sci 11:92–103

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gabor EM, Janssen DB (2004) Increasing the synthetic performance of penicillin acylase PAS2 by structure-inspired semi-random mutagenesis. Protein Eng Des Sel 17(7):571–579

    PubMed  CAS  Google Scholar 

  • Gabor EM, de Vries EJ, Janssen DB (2005) A novel penicillin acylase from the environmental gene pool with improved synthetic properties. Enzyme Microb Technol 36:182–190

    Google Scholar 

  • Giordano RC, Ribeiro MPA, Giordano RLC (2006) Kinetics of β-lactam antibiotics synthesis by penicillin G acylase (PGA) from the viewpoint of the industrial enzymatic reactor optimization. Biotechnol Adv 24:27–41

    PubMed  CAS  Google Scholar 

  • Gonçalves LRB, Giordano RLC, Giordano RC (2005) Mathematical modeling of batch and semibatch reactors for the enzymic synthesis of amoxicillin. Process Biochem 40:247–256

    Google Scholar 

  • Gong X, Su E, Wang P, Wei D (2011) Alcaligenes faecalis penicillin G acylase-catalyzed enantioselective acylation of dl-phenylalanine and derivatives in aqueous medium. Tetrahedron Lett 52:5398–5402

    CAS  Google Scholar 

  • Grinberg VY, Burova TV, Grinberg NV, Shcherbakova TA, Guranda DT, Chilov GG, Švedas VK (2008) Thermodynamic and kinetic stability of penicillin acylase from Escherichia coli. Biochim Biophys Acta 1784(5):736–746

    PubMed  CAS  Google Scholar 

  • Grulich M, Štěpánek V, Kyslík P (2013) Perspectives and industrial potential of PGA selectivity and promiscuity. Biotechnol Adv 31(8):1458–1472

    PubMed  CAS  Google Scholar 

  • Guranda DT, Khimiuk AI, van Langen LM, van Rantwijk F, Sheldon RA (2004) An easy-on, easy-off protecting group for the enzymatic resolution of 1-phenylethylamine in an aqueous medium. Tetrahedron Asymmetry 15:2901–2906

    CAS  Google Scholar 

  • Harris DM, Westerlaken I, Schipper D, van der Krogt ZA, Gombert AK, Sutherland J, Raamsdonk LM, van den Berg MA, Bovenberg RA, Pronk JT, Duran JM (2009) Engineering of Penicillium chrysogenum for fermentative production of a novel carbamoylated cephem antibiotic precursor. Metab Eng 11:125–137

    PubMed  CAS  Google Scholar 

  • Hernández-Jústiz O, Fernandez-Lafuente R, Terrini M, Guisan JM (1998) Use of aqueous two-phase systems for in situ extraction of water soluble antibiotics during their synthesis by enzymes immobilized on porous supports. Biotechnol Bioeng 59:73–79

    PubMed  Google Scholar 

  • Illanes A, Fajardo A (2001) Kinetically controlled synthesis of ampicillin with immobilized penicillin acylase in the presence of organic cosolvents. J Mol Catal B Enzym 11(4):587–595

    CAS  Google Scholar 

  • Illanes A, Wilson L, Aguirre C (2009) Synthesis of cephalexin in aqueous medium with carrier-bound and carrier-free penicillin acylase biocatalysts. Appl Biochem Biotechnol 157(1):98–110

    PubMed  CAS  Google Scholar 

  • Jager SAW, Jekel PA, Janssen DB (2007) Hybrid penicillin acylases with improved properties for synthesis of β-lactam antibiotics. Enzyme Microb Technol 40:1335–1344

    Google Scholar 

  • Jager SAW, Shapovalova IV, Jekel PA, Alkema WB, Svedas VK, Janssen DB (2008) Saturation mutagenesis reveals the importance of residues αR145 and αF146 of penicillin acylase in the synthesis of β-lactam antibiotics. J Biotechnol 133:18–26

    PubMed  CAS  Google Scholar 

  • Kadereit D, Waldmann H (2001) Enzymatic protecting group-techniques. Chem Rev 101:3367–3396

    PubMed  CAS  Google Scholar 

  • Kallenberg AI, van Ratwijk F, Sheldon RA (2005) Immobilization of penicillin G acylase: the key to optimum performance. Adv Synth Catal 347:905–926

    CAS  Google Scholar 

  • Kato K, Kawahara K, Takahashi T (1980) Enzymatic synthesis of amoxicillin by the cell-bound α-amino acid ester hydrolase of Xanthomonas citri. Agric Biol Chem 44(4):821–825

    CAS  Google Scholar 

  • Kim MG, Lee SB (1996) Penicillin acylase-catalyzed synthesis of pivampicillin: effect of reaction variables and organic cosolvents. J Mol Catal B Enzym 1:71–80

    CAS  Google Scholar 

  • Koreishi M, Tani K, Ise Y, Imanaka H, Imamura K, Nakanishi K (2007) Enzymatic synthesis of beta-lactam antibiotics and N-fatty-acylated amino compounds by the acyl-transfer reaction catalyzed by penicillin V acylase from Streptomyces mobaraensis. Biosci Biotechnol Biochem 71:1582–1586

    PubMed  CAS  Google Scholar 

  • Kumar A, Prabhune A, Suresh GC, Pundle A (2008) Characterization of smallest active monomeric penicillin V acylase from new source: a yeast, Rhodotorula aurantiaca (NCIM 3425). Process Biochem 43:961–967

    CAS  Google Scholar 

  • Kumaraguru T, Fadnavis NV (2012) Resolution of racemic 4-hydroxy-2-cyclopentenone with immobilized penicilin G acylase. Tetrahedron Asymmetry 23(10):775–779

    CAS  Google Scholar 

  • Lee KJ (2012) Immobilization of enzyme on hydrophobic room temperature solid-phase ionic liquids and its use for bicatalytic transesterification in organic solvent: remarkably enhanced activity of lipase. Bull Korean Chem Soc 33:3458–3460

    CAS  Google Scholar 

  • Li D, Cheng S, Wei D, Ren Y, Zhang D (2008a) Production of enantiomerically pure (S)-beta-phenylalanine by penicillin G acylase from Escherichia coli in aqueous medium. Biotechnol Lett 29(12):1825–1830

    Google Scholar 

  • Li D, Zhang Y, Cheng S, Gao Q, Wei D (2008b) Enhanced enzymatic production of cephalexin at high substrate concentration with in situ product removal by complexation. Food Technol Biotechnol 46(4):461–466

    CAS  Google Scholar 

  • Li D, Ji L, Wang X, Wei D (2013) Enantioselective acylation of β-phenylalanine acid and its derivatives catalyzed by penicillin G acylase from Alcaligenes faecalis. Prep Biochem Biotechnol 43(2):207–216

    PubMed  CAS  Google Scholar 

  • Lin YH, Hsiao HC, Chou CP (2002) Strain improvement to enhance the production of recombinant penicillin acylase in high-cell-density Escherichia coli cultures. Biotechnol Prog 18(6):1458–1461

    PubMed  CAS  Google Scholar 

  • Lindsay JP, Clark DS, Dordick JS (2002) Penicillin amidase is activated for use in nonaqueous media by lyophilizing in the presence of potassium chloride. Enzyme Microb Technol 31:193–197

    Google Scholar 

  • Liu YC, Chang WM, Lee CY (1999) Effect of oxygen enrichment aeration on penicillin G acylase production in high cell density culture of recombinant E. coli. Bioprocess Eng 21(3):227–230

    CAS  Google Scholar 

  • Liu SL, Song QX, Wei DZ, Zhang YW, Wang XD (2006) Preparation of optically pure tert-leucine by penicillin G acylase-catalyzed resolution. Prep Biochem Biotechnol 36:235–241

    PubMed  CAS  Google Scholar 

  • Liu B, Wu Q, Lv D, Lin X (2011) Modulating the synthetase activity of penicillin G acylase in organic media by addition of N-methyimidazole: using vinyl acetate as activated acyl donor. J Biotechnol 153:111–115

    PubMed  CAS  Google Scholar 

  • Marešová H, Marková Z, Valešová R, Sklenář J, Kyslík P (2010) Heterologous expression of leader-less pga gene in Pichia pastoris: intracellular production of prokaryotic enzyme. BMC Biotechnol 10:7

    PubMed Central  PubMed  Google Scholar 

  • Margolin AL, Svedas VKS, Berezin IV (1980) Substrate specificity of penicillin amidase from Escherichia coli. Biochim Biophys Acta 616:283–289

    PubMed  CAS  Google Scholar 

  • Massolini G, Calleri E, Lavecchia A, Loiodice F, Lubda D, Temporini C, Fracchiolla G, Tortorella P, Novellino E, Caccialanza G (2003) Enantioselective hydrolysis of some 2-aryloxyalkanoic acid methyl esters and isosteric analogues using a penicilin G acylase-based HPLC monolithic silica column. Anal Chem 75:535–542

    PubMed  CAS  Google Scholar 

  • McVey CE, Walsh MA, Dodson GG, Wilson KS, Brannigan JA (2001) Crystal structures of penicillin acylase enzyme–substrate complexes: structural insights into the catalytic mechanism. J Mol Biol 313(1):139–150

    PubMed  CAS  Google Scholar 

  • Montes T, Grazú V, López-Gallego F, Hermoso JA, García JL, Manso I, Galán B, González R, Fernández-Lafuente R, Guisán JM (2007) Genetic modification of the penicillin G acylase surface to improve its reversible immobilization on ionic exchangers. Appl Environ Microbiol 73(1):312–319

    PubMed Central  PubMed  CAS  Google Scholar 

  • Monti D, Carrea G, Riva S, Baldaro E, Frare G (2000) Characterization of an industrial biocatalyst: immobilized glutaryl-7-ACA acylase. Biotechnol Bioeng 70:239–244

    PubMed  CAS  Google Scholar 

  • Morimoto S, Nomura H, Fugono T, Azuma T, Minami I, Hori M, Masuda T (1972) Semisynthetic β-lactam antibiotics. 2. Synthesis and properties of d-and l-β-sulfobenzylpenicillins. J Med Chem 15(11):1108–1111

    PubMed  CAS  Google Scholar 

  • Oh B, Kim K, Park J, Yoon J, Han D, Kim Y (2004) Modifying the substrate specificity of penicillin G acylase to cephalosporin acylase by mutating active-site residues. Biochem Biophys Res Commun 319:486–492

    PubMed  CAS  Google Scholar 

  • Olsson A, Hagstrom T, Nilsson B, Unhen M, Gatenbeck S (1985) Molecular cloning of Bacillus sphaericus penicillin V amidase gene and its expression in Escherichia coli and Bacillus subtilis. Appl Environ Microbiol 49:1084–1089

    PubMed Central  PubMed  CAS  Google Scholar 

  • Orr V, Scharer J, Moo-Young M, Honeyman CH, Fenner D, Crossley L, Suen SY, Chou CP (2012) Integrated developement of an effective bioprocess for extracellular production of penicillin G acylase in Escherichia coli and its subsequent one-step purification. J Biotechnol 161:19–26

    PubMed  CAS  Google Scholar 

  • Ospina SS, Lopez-Munguia A, Gonzalez RL, Quintero R (1992) Characterization and use of a penicillin acylase biocatalyst. J Chem Technol Biotechnol 53(2):205–214

    PubMed  CAS  Google Scholar 

  • Ozcengiz G, Demain AL (2013) Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation. Biotechnol Adv 31(2):287–311

    PubMed  CAS  Google Scholar 

  • Pan J, Wang L, Li D, Ye L (2013) Synthesis of cefatrizine by recombinant α-amino acid ester hydrolase. Chin J Biotechnol 29(4):501–509

    CAS  Google Scholar 

  • Park CB, Lee SB, Ryu DDY (2000) Penicillin acylase-catalyzed synthesis of cefazolin in water–solvent mixtures: enhancement effect of ethyl acetate and carbon tetrachloride on the synthetic yield. J Mol Catal B Enzym 9:275–281

    CAS  Google Scholar 

  • Polderman-Tijmes JJ, Jeckel PA, de Vries EJ, van Merode AE, Floris R, van der Laan JM, Sonke T, Janssen DB (2002a) Cloning, sequence analysis, and expression in Eschirichia coli of the gene encoding an α-amino acid ester hydrolase from Acetobacter turbidans. Appl Eviron Microbiol 68:211–218

    CAS  Google Scholar 

  • Polderman-Tijmes JJ, Jeckel PA, Jeronimus-Stratingh CM, Bruins AP, van der Laan JM, Sonke T, Janssen DB (2002b) Identification of the catalytic residues of α-amino acid ester hydrolase from Acetobacter turbidans by labeling and site-directed mutagenesis. J Biol Chem 277:29474–29482

    Google Scholar 

  • Pollegioni L, Lorenzi S, Rosini E, Marcone GL, Molla G, Verga R, Cabri W, Pilone MS (2005) Evolution of an acylase active on cephalosporin C. Protein Sci 14:3064–3076

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rajendhran J, Gunasekaran P (2004) Recent biotechnological interventions for develo** improved penicillin G acylases. J Biosci Bioeng 97(1):1–13

    PubMed  CAS  Google Scholar 

  • Ribeiro MP, Ferreira AL, Giordano RL, Giordano RC (2005) Selectivity of the enzymatic synthesis of ampicillin by E. coli PGA in the presence of high concentrations of substrates. J Mol Catal B Enzym 33:81–86

    CAS  Google Scholar 

  • Robin J, Jacobsen M, Beyer M, Noorman H, Nielsen J (2001) Physiological characterisation of Penicillium chrysogenum strains expressing the expandase gene from Streptomyces clavuligerus during batch cultivations. Growth and adipoyl-7-aminodeacetoxycephalosporanic acid production. Appl Microbiol Biotechnol 57:357–362

    PubMed  CAS  Google Scholar 

  • Rocchietti S, Urrutia ASV, Pregnolato M, Tagliani A, Guisan JM, Fernandez-Lafuente (2002) Influence of the enzyme derivative preparation and substrate structure on the enantioselectivity penicillin G acylase. Enzyme Microb Technol 31:88–93

  • Roche D, Prasad K, Repic O (1999) Enantioselective acylation of ß-aminoesters using penicillin G acylase in organic solvents. Tetrahedron Lett 40:3665–3668

    CAS  Google Scholar 

  • Sakaguchi K, Murao S (1950) A preliminary report on a new enzyme, “penicillin-amidase”. J Agric Chem Soc Jpn 23:411

    CAS  Google Scholar 

  • Schroën CGPH, Nierstrasz VA, Kroon PJ, Bosma R, Janssen AEM, Beeftink HH, Tramper J (1999) Thermodynamically controlled synthesis of β-lactam antibiotics. Equilibrium concentrations and side-chain properties. Enzyme Microb Technol 24(8–9):498–506

    Google Scholar 

  • Schroën CGPH, Eldin MSM, Janssen AEM, Mita GD, Tramper J (2001) Cephalexin synthesis by immobilised penicillin G acylase under non-isothermal conditions: reduction of diffusion limitation. J Mol Catal B Enzym 15(4–6):163–172

    Google Scholar 

  • Schroën CGPH, Nierstrasz VA, Bosma R, Kroon PJ, Tjeerdsma PS, DeVroom E, VanderLaan JM, Moody HM, Beeftink HH, Janssen AEM, Tramper J (2002) Integrated reactor concepts for the enzymatic kinetic synthesis of cephalexin. Biotechnol Bioeng 80:144–155

    PubMed  Google Scholar 

  • Schumacher G, Sizmann D, Haug H, Buckel P, Bock A (1986) Penicillin acylase from E. coli: unique gene–protein relation. Nucleic Acids Res 14:5713–5727

    PubMed Central  PubMed  CAS  Google Scholar 

  • Senerovic L, Stankovic N, Pizzo P, Basso A, Gardossi L, Vasiljevic B, Ljubijankić G, Tisminetzky S, Degrassi G (2006) High-level production and covalent immobilization of Providencia rettgeri penicillin G acylase (PAC) from recombinant Pichia pastoris for the development of a novel and stable biocatalyst of industrial applicability. Biotechnol Bioeng 93:344–354

    PubMed  CAS  Google Scholar 

  • Shaw SY, Shyu JC, Hsieh YW, Yeh HJ (2000) Enzymatic synthesis of cephalothin by penicillin acylase. Enzyme Microb Technol 26:142–151

    Google Scholar 

  • Sheldon RA (2008) E factors, green chemistry, and catalysis: an odysey. Chem Commun 29:3352–3365

    Google Scholar 

  • Sheldon RA (2011) Characteristic features and biotechnological applications of cross-linked enzyme aggregates (CLEAs). Appl Microbiol Biotechnol 92:467–477

    PubMed Central  PubMed  CAS  Google Scholar 

  • Shewale JG, Sudhakaran VK (1997) Penicillin V acylase: its potential in the production of 6-amino penicillanic acid. Enzyme Microb Technol 20:402–410

    Google Scholar 

  • Shin YC, Jeon J, Jung KH, Mark MR, Kim Y (2005) Cephalosporin C acylase mutant and method for preparing 7-ACA using same. WO 2005/014821 A1

  • Sio CF, Quax WJ (2004) Improved β-lactam acylases and their use as industrial biocatalysts. Curr Opin Biotechnol 15:349–355

    PubMed  CAS  Google Scholar 

  • Sio CF, Riemens AM, van der Laan JM, Verhaert RMD, Quax WJ (2002) Directed evolution of a glutaryl acylase into an adipyl acylase. Eur J Biochem 269:4495–4504

    PubMed  CAS  Google Scholar 

  • Solano DN, Honos P, Hernaíz MJ, Alcantara AR, Sanchez-Montero JM (2012) Industrial biotransformations in the synthesis of building blocks leasing to enantiopure drugs. Bioresour Technol 115:196–207

    Google Scholar 

  • Srirangan K, Orr V, Akawi L, Westbrook A, Moo-Young M, Chou CP (2013) Biotechnological advances on penicillin G acylase: pharmaceutical implications, unique expression mechanism and production strategies. Biotechnol Adv 31(8):1319–1332

    PubMed  CAS  Google Scholar 

  • Suresh CG, Pundle AV, SivaRaman H, Rao KN, Brannigan JA, McVey CE, Verma CS, Dauter Z, Dodson EJ, Dodson GG (1999) Penicillin V acylase crystal structure reveals new Ntn-hydrolase family members. Nat Struct Mol Biol 6:414–416

    CAS  Google Scholar 

  • Švedas VK, Beltser AL (1998) Totally enzymatic synthesis of peptides: penicillin acylase-catalysed protection and deprotection of amido groups as important building blocks of this strategy. Enzyme Eng 864:524–527

    Google Scholar 

  • Takahashi T, Yamazaki Y, Kato K, Isono M (1972) Enzymatic synthesis of cephalosporins. J Am Chem Soc 94:4035–4037

    PubMed  CAS  Google Scholar 

  • Takahashi T, Yamazaki Y, Kato K (1974) Substrate specificity of an α-amino acid ester hydrolase produced by Acetobacter turbidans A.T.C.C. 9325. Biochem J 137:497–503

    PubMed Central  PubMed  CAS  Google Scholar 

  • Terreni M, Tchamkam JG, Sarnataro U, Rocchietti S, Fernández-Lafuente R, Guisán JM (2005) Influence of substrate structure on PGA-catalyzed acylations. Evaluation of different approaches for the enzymatic synthesis of cefonicid. Adv Synth Catal 347:121–128

    CAS  Google Scholar 

  • Terreni M, Ubiali D, Bavaro T, Pregnolato M, Fernández-Lafuente R, Guisán JM (2007) Enzymatic synthesis of cephalosporins. The immobilized acylase from Arthrobacter viscosus: a new useful biocatalyst. Appl Microbiol Biotechnol 77(3):579–587

    Google Scholar 

  • Thykaer J, Nielsen J (2003) Metabolic engineering of β-lactam production. Metab Eng 5(1):56–69

    PubMed  CAS  Google Scholar 

  • Tishkov VI, Savin SS, Yasnaya AS (2010) Protein engineering of penicillin acylase. Acta Nat 2(3):47–61

    CAS  Google Scholar 

  • Topgi RS, Ng JS, Landis B, Wang P, Behling JR (1999) Use of enzyme penicillin acylase in selective amidation/amide hydrolysis to resolve ethyl 3-amino-4-pentynoate isomers. Bioorg Med Chem 7:2221–2229

    PubMed  CAS  Google Scholar 

  • van de Sandt EJAX, de Vroom E (2000) Innovations in cephalosporin and penicillin production: painting the antibiotics industry green. Chim Oggi 18:72–75

    Google Scholar 

  • van den Berg MA, Westerlaken I, Leeflang C, Kerkman R, Bovenberg RAL (2007) Functional characterization of the penicillin biosynthetic gene cluster of Penicillium chrysogenum Wisconsin 54-1255. Fungal Genet Biol 44:830–844

    PubMed  Google Scholar 

  • van Roon JL, Schroën CG, Tramper J, Beeftink HH (2007) Biocatalysts: measurement, modelling and design of heterogeneity. Biotechnol Adv 25(2):137–147

    PubMed  Google Scholar 

  • Venkataiah M, Reddipalli G, Jasti LS, Fadnawis NW (2011) Chemo-enzymatic synthesis of the azasugars 1,4-dideoxyallonojirimycin and 1,4-dideoxymannojirimycin. Tetrahedron Asymmetry 22:1855–1860

    CAS  Google Scholar 

  • Volpato G, Rodrigues RC, Fernandez-Lafuente R (2010) Use of enzymes in the production of semi-synthetic penicillins and cephalosporins: drawbacks and perspectives. Curr Med Chem 17:3855–3873

    PubMed  CAS  Google Scholar 

  • Wang J, Zhang Q, Huang H, Yuan Z, Ding D, Yang S, Jiang W (2007) Increasing synthetic performance of penicillin G acylase from Bacillus megaterium by site-directed mutagenesis. Appl Microbiol Biotechnol 74(5):1023–1030

    PubMed  CAS  Google Scholar 

  • Wang JL, Li X, **e HY, Liu BK, Lin XF (2010) Hydrolase-catalyzed fast Henry reaction of nitroalkanes and aldehydes in organic media. J Biotechnol 145:240–243

    PubMed  CAS  Google Scholar 

  • Wang L, Ye LJ, Pan Y, Cao Y (2012) Two plate-based colorimetric assays for screening α-amino acid ester hydrolase with high synthesis/hydrolysis ratio. Enzyme Microb Technol 51:107–112

    Google Scholar 

  • Ward OP (2012) Production of recombinant proteins by filamentous fungi. Biotechnol Adv 30:1119–1139

    PubMed  CAS  Google Scholar 

  • Wei D, Yang L, Song Q (2003) Effect of temperature on the enzymatic synthesis of cefaclor with in situ product removal. J Mol Catal B Enzym 26:99–104

    CAS  Google Scholar 

  • Westers L, Westers H, Quax WJ (2004) Bacillus subtilis as cell factory for pharmaceutical proteins: a biotechnological approach to optimize the host organism. Biochim Biophys Acta 1694:299–310

    PubMed  CAS  Google Scholar 

  • Wu WB, Wang N, Xu JM, Wu Q, Lin XF (2005) Penicillin G acylase catalyzed Markovnikov addition of allopurinol to vinyl ester. Chem Commun 18:2348–2350

    Google Scholar 

  • Wu WB, Xu JM, Wu Q, Lv DS, Lin XF (2006) Promiscuous acylases-catalyzed Markovnikov addition of N-heterocycles to vinyl esters in organic media. Adv Synth Catal 348:487–492

    CAS  Google Scholar 

  • Wu Q, Chen CX, Du LL, Lin XF (2010) Enzymatic synthesis of amoxicillin via a one-pot enzymatic hydrolysis and condensation cascade process in the presence of organic co-solvents. Appl Biochem Biotechnol 160:2026–2035

    PubMed  CAS  Google Scholar 

  • Yang L, Wei DZ (2003) Enhanced enzymatic synthesis of a semi-synthetic cephalosporin, cefaclor, with in situ product removal. Biotechnol Lett 25(14):1195–1198

    PubMed  CAS  Google Scholar 

  • Yang Y, Biedendieck R, Wang W, Gamer M, Malten M, Jahn D, Deckwer WD (2006) High yield recombinant penicillin G amidase production and export into the growth medium using Bacillus megaterium. Microb Cell Factories 5:36

    Google Scholar 

  • Yang YH, Aloysius H, Inoyama D, Chen Y, Hu LQ (2011) Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharmacol Sin B 1(3):143–159

    CAS  Google Scholar 

  • Yao Y, Lalonde JJ (2003) Unexpected enantioselectivity and activity of penicillin acylase in the resolution of methyl 2,2-dimethyl-1,3-dioxane-4-carboxylate. J Mol Catal B Enzym 22:55–59

    CAS  Google Scholar 

  • Ye LY, Wang L, Pan Y, Cao Y (2012) Changing the specificity of α-amino acid ester hydrolase toward para-hydroxyl cephalosporins synthesis by side-directed saturation mutagenesis. Biotechnol Lett 34:1719–1724

    PubMed  CAS  Google Scholar 

  • Youshko MI, Chilov GG, Shcherbakova TA, Švedas VK (2002) Quantitative characterization of the nucleophile reactivity in penicillin acylase-catalyzed acyl transfer reactions. Biochim Biophys Acta 1599:134–140

    PubMed  CAS  Google Scholar 

  • Youshko MI, Moody HM, Bukhanov AL, Boosten WH, Svedas VK (2004) Penicillin acylase-catalyzed synthesis of β-lactam antibiotics in highly condensed aqueous systems: beneficial impact of kinetic substrate supersaturation. Biotechnol Bioeng 85:323–329

    PubMed  CAS  Google Scholar 

  • Zahel T, Boniello B, Nidetzky B (2013) Real-time measurement and modeling of intraparticle pH gradient formation in immobilized cephalosporin C amidase. Proc Biochem 48:593–604

    CAS  Google Scholar 

  • Zhang M, Shi M, Zhou Z, Yang S, Yuan Z, Ye Q (2006) Production of Alcaligenes faecalis penicillin G acylase in Bacillus subtilis WB600 (pMA5) fed with partially hydrolyzed starch. Enzyme Microb Technol 39(4):555–560

    Google Scholar 

  • Zhang YW, Liu SL, Wei DZ, Liu RJ, Xu XM (2008) Kinetically controlled synthesis of cefaclor with immobilized penicillin acylase in the presence of organic cosolvents. Chem Biochem Eng Q 22(3):349–354

    Google Scholar 

  • Zhou Z, Zhang AH, Wang JR, Chen ML, Li RB, Yang S, Yuan ZY (2003) Improving the specific synthetic activity of a penicillin G acylase using DNA family shuffling. Acta Biochim Biophys Sin 35(6):573–579

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by the long-term research development project no. RVO 61388971 of the Institute of Microbiology of the Academy of Sciences of the Czech Republic (ASCR), v.v.i.

Author information

Authors and Affiliations

  1. Laboratory of Enzyme Technology, Institute of Microbiology v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220, Prague 4, Czech Republic

    Helena Marešová, Martina Plačková, Michal Grulich & Pavel Kyslík

  2. Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 12840, Prague 2, Czech Republic

    Martina Plačková

  3. Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 12840, Prague 2, Czech Republic

    Michal Grulich

Authors
  1. Helena Marešová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Plačková
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michal Grulich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pavel Kyslík
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pavel Kyslík.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marešová, H., Plačková, M., Grulich, M. et al. Current state and perspectives of penicillin G acylase-based biocatalyses. Appl Microbiol Biotechnol 98, 2867–2879 (2014). https://doi.org/10.1007/s00253-013-5492-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-013-5492-7

Keywords

Search

Navigation