Biomics

Studies of cyclic oligosaccharides from six, seven and eight glucose residues, designated as alpha-, beta- and gamma-cyclodextrins, respectively, and everything related to them have been going on for 130 years. In this review, the history of the study of these molecules is briefly considered. The interest in cyclodextrins is caused by their ability to form inclusion complexes with a number of organic and inorganic compounds, radically changing some of their properties. This is widely used in the pharmaceutical, cosmetic and food industries, and beta-cyclodextrin is even registered as a food additive E459. Cyclodextrins are obtained from starch under the action of cyclodextringlucanotransferase (CGTase) enzymes, a characteristic feature of which is their non-strict specificity in relation to the types of oligosaccharides produced. The main producers of these enzymes are a group of bacteria of the order Bacillales, which unites several families (Paenibacillaceae, Bacillaceae, Thermoactynomicetaceae, etc.), but in last years CGTases have been found in a wide range of bacteria and archaea. The genetic engineering of CGTases began in the middle of 1980s, after the CGTase gene from Paenibacillus macerans (formerly Bacillus macerans) was cloned and sequenced for the first time, and during this period rather noticeable progress was made in understanding the organization and functioning of these enzymes, including using X-ray diffraction analysis. With the help of site-directed mutagenesis, error-prone PCR, as well as by creating chimeric forms of these enzymes, certain successes have been achieved in recent decades in changing (improving) the specificity of their action. Suitable leader peptides are used to increase the synthesis and secretion of genetically engineered CGTases, and various heterologous producers are also proposed, including the bacteria Escherichia coli, B.subtilis, Lactococcus lactis and the methylotrophic yeast Koagataella phaffii.

Cyclomaltodextringlucanotransferase, CGTase, gene, sequencing, cyclodextrin, starch, producer strain

1. Abdalla M., Hassanin H.A.M., Yao X., Iqbal M.W., Karrar E., Jiang B. Genetic and biochemical characterization of thermophilic β-cyclodextrin glucanotransferase from Gracilibacillus alcaliphilus SK51.001. Science of Food and Agriculture. 2021. V.101(8). P. 3308-3318

2. Ash C., Priest F.G., Collins M.D. Molecular identification of rRNA group 3 bacilli (Ash, Farrow, Wallbanks and Collins) using a PCR probe test. Proposal for the creation of a new genus Paenibacillus. Antonie Van Leeuwenhoek. 1993-1994. V.64(3-4). P. 253-260. doi: 10.1007/BF00873085.

3. Ban X., Gu Z., Li C., Huang M., Cheng L., Hong Y., Li Z. Mutations at calcium binding site III in cyclodextrin glycosyltransferase improve β-cyclodextrin specificity. Int J Biol Macromol. 2015. V.76. P.224-229. doi: 10.1016/j.ijbiomac.2015.02.036.

4. Bender H. Branched saccharides formed by the action of His-modified cyclodextrin glycosyltransferase from Klebsiella pneumoniae M 5 al on starch. Carbohydr Res. 1991. V.222. P.239-244. doi: 10.1016/0008-6215(91)89022-8

5. Bender H. Studies of the mechanism of the cyclisation reaction catalysed by the wildtype and a truncated alpha-cyclodextrin glycosyltransferase from Klebsiella pneumoniae strain M 5 al, and the betacyclodextrin glycosyltransferase from Bacillus circulans strain 8. Carbohydr Res. 1990. V.206(2). P.257-267. doi: 10.1016/0008-6215(90)80065-b

6. Bikbulatova S.M., Chemeris A.V., Usanov N.G, Vahitov. V.A. Establishment of the phylogenetic relationship between the microbial producers of cyclodextrin glucanotransferases using their complete amino acid sequences. Microbiology (Mikrobiologiya). 2000. V. 69(5). P. 575-581.

7. Binder F., Huber O., Böck A. Cyclodextringlycosyltransferase from Klebsiella pneumoniae M5a1: cloning, nucleotide sequence and expression. Gene. 1986. V.47(2-3). P.269-277. doi: 10.1016/0378-1119(86)90070-3

8. Castillo J., Caminata Landriel S., Sánchez Costa M., Taboga O.A., Berenguer J., Hidalgo A., Ferrarotti S.A., Costa H. A single mutation in cyclodextrin glycosyltransferase from Paenibacillus barengoltzii changes cyclodextrin and maltooligosaccharides production. Protein Eng Des Sel. 2018. V. 31(10). P. 399-407. doi: 10.1093/protein/gzy034.

9. Chemeris A.V., Bikbulatova S.M., Usanov N.G, Vakhitov. V.A. Molekuljarnoe klonirovanie, opredelenie nukleotidnoj posledovatel'nosti gena alphaciklodekstringljukanotransferazy Paenibacillus macerans shtamma IB-7 i sravnitel'nyj analiz pervichnoj struktury alpha- i beta-CGTaz. Biotehnologija. 1999. No.6. S.11-18. [Molecular cloning, determination of the nucleotide
sequence of the gene alphacyclodextringlucanotransferase Paenibacillus macerans strain IB-7 and comparative analysis of the primary structure of alpha- and beta-CGTases] (In Russian)

10. Chen F., Xie T., Yue Y., Qian S., Chao Y., Pei J. Molecular dynamic analysis of mutant Y195I αcyclodextrin glycosyltransferase with switched product specificity from α-cyclodextrin to γ-cyclodextrin. J Mol Model. 2015. V.21(8). P.208. doi: 10.1007/s00894-015-2734-x.

11. Chen S., Li Z, Gu Z., Hong Y., Cheng L., Holler T.P., Li C. Leu600 mutations decrease product inhibition of the β-cyclodextrin glycosyltransferase from Bacillus circulans STB01. Int J Biol Macromol. 2018. V.115. P.1194-1201. doi: 10.1016/j.ijbiomac.2018.05.006.

12. Chen S., Li Z., Gu Z., Hong Y., Cheng L., Li C. Variants at position 603 of the CGTase from Bacillus circulans STB01 for reducing product inhibition. Int J Biol Macromol. 2019. V.1(136). P.460-468. doi: 10.1016/j.ijbiomac.2019.05.160.

13. Cramer F. Einschlußverbindungen der Cyclodextrine. Angewandte chemie. 1952. V.64(5). P.136-136 doi: 10.1002/ange.19520640506

14. Cramer F. Über Einschlußverbindungen, I. Mitteil.: Additionsverbindungen der Cycloamylosen. Chemische berichte. 1951. V.84(9). P.851-854. doi: 10.1002/cber.19510840912

15. Crini G. Review: a history of cyclodextrins. Chem Rev. 2014. V.114(21). P. 10940-10975. doi: 10.1021/cr500081p

16. Deng C., Li J., Shin H.D., Du G., Chen J., Liu L. Efficient expression of cyclodextrin glycosyltransferase from Geobacillus stearothermophilus in Escherichia coli by promoter engineering and downstream box evolution. J Biotechnol. 2018. V.266. P.77-83. doi: 10.1016/j.jbiotec.2017.12.009.

17. Fedorova P.Ju., Usanov N.G., Gil'vanova E.A. Sravnenie kineticheskih svojstv razlichnyh ciklodekstringljukanotransferaz. Izvestija Samarskogo nauchnogo centra Rossijskoj akademii nauk. 2011. V. 13, No.5(3). S. 203-206. [Comparison of kinetic properties of various cyclodextringlucanotransferases] (In Russian)

18. Fedorova P.Ju., Gil'vanova E.A., Aktuganov G.Je., Usanov N.G. Ochistka i svojstva ciklodekstringljukanotransferazy bakterij Paenibacillus ehimensis VKM B-2680D. Biotehnologija. 2012. № 4. S. 31-38. [Purification and properties of cyclodextringlucanotransferase of bacteria Paenibacillus ehimensis VCM B-2680D] (In Russian)

19. French D. Cyclodextrin Transglycosylase (Bacillus macerans Amylase): Gn ⇄ G(n−6) + α (Eq. 1); Gn ⇄ G(n−7) + β (Eq. 2), etc.; Cyclization → ←Coupling;Gn + Gm ⇄ G(n+x)) + G(m−x) (Eq. 3); Homologizing or disproportionation. Methods in Enzymology. 1962. V.5. P.148-155. doi: 10.1016/S0076-6879(62)05197-6

20. Freudenberg K., Cramer F. Die constitution der Schardinger-dextrine dextrine-alpha, dextrin-beta and dextrin-gamma. Z. Naturforsch. 1948. V. 3. P.464–464.

21. Freudenberg, K., Cramer, F. Über die Schardinger-dextrine aus stärke. Chem. Ber. Recl. 1950. V.83. P. 296–304.

22. Gimenez G.G., Costa H., de Lima Neto Q.A., Fernandez M.A., Ferrarotti S.A., Matioli G. Sequencing, cloning, and heterologous expression of cyclomaltodextrin glucanotransferase of Bacillus firmus strain 37 in Bacillus subtilis WB800. Bioprocess Biosyst Eng. 2019. V.42(4). P.621-629. doi: 10.1007/s00449-018-02068-4.

23. Gilvanova E.A., Milman P.U. Skrining mikroorganizmov-producentov γciklodekstringlyukanotransferaz // Izvestiya Ufimskogo
nauchnogo centra RAN. 2015. № 4(1). S. 29-31. [Screening of microorganisms producing γcyclodextringlucanotransferases] (In Russian)

24. Goo B.G., Hwang Y.J., Park J.K. Bacillus thuringiensis: a specific gamma-cyclodextrin producer strain. Carbohydr Res. 2014. V. 11(386). P. 12-17. doi: 10.1016/j.carres.2013.12.005.

25. Han R, Li J, Shin H.D, Chen R.R, Du G, Liu L, Chen J. Recent advances in discovery, heterologous expression, and molecular engineering of cyclodextrin glycosyltransferase for versatile applications. Biotechnol Adv. 2014. V.32(2). P.415-28. doi: 10.1016/j.biotechadv.2013.12.004.

26. Hao J.H., Huang L.P., Chen X.T., Sun J.J., Liu J.Z., Wang W., Sun M. Identification, cloning and expression analysis of an alpha-CGTase produced by stain Y112. Protein Expr Purif. 2017. V.140. P.8-15. doi: 10.1016/j.pep.2017.07.015.

27. Huang M., Li C., Gu Z., Cheng L., Hong Y., Li Z. Mutations in cyclodextrin glycosyltransferase from Bacillus circulans enhance β-cyclization activity and βcyclodextrin production. J Agric Food Chem. 2014. V. 62(46). P. 11209-11214. doi: 10.1021/jf503523z.

28. Ismail A., Illias R.M. Site-saturation mutagenesis of mutant L-asparaginase II signal peptide hydrophobic region for improved excretion of cyclodextrin glucanotransferase. J Ind Microbiol Biotechnol. 2017. V.44(12). P.1627-1641. doi: 10.1007/s10295-017-1980-6.

29. Jemli S., Jaoua M., Bejar S. US132 Cyclodextrin Glucanotransferase Engineering by Random Mutagenesis for an Anti-Staling Purpose. Mol Biotechnol. 2016. V.58(8-9). P.551-557. doi: 10.1007/s12033-016-9952-z.

30. Jia X., Guo Y., Lin X., You M., Lin C., Chen L., Chen J. Fusion of a family 20 carbohydrate-binding module (CBM20) with cyclodextrin glycosyltransferase of Geobacillus sp. CHB1 improves catalytic efficiency. J Basic Microbiol. 2017. V.57(6). P.471-480. doi: 10.1002/jobm.201600628.

31. Jiang Y., Zhou J., Wu R., Xin F., Zhang W., Fang Y., Ma J., Dong W., Jiang M. Heterologous expression of cyclodextrin glycosyltransferase from Paenibacillus macerans in Escherichia coli and its application in 2-O-α-D-glucopyranosyl-L-ascorbic acid
production. BMC Biotechnol. 2018. V.18(1). P.53. doi: 10.1186/s12896-018-0463-9.

32. Kitahata S., Okada S. Studies on cyclodextrin glycosyltransferase. IV. Enzymatic synthesis of 3-Oalpha-D-glucopyranosyl-L-sorbose and 4-O-alpha-Dglucopyranosyl-D-xylose using cyclodextrin glycosyltransferase. Biochem. 1976. V.79(3). P. 641-648. doi: 10.1093/oxfordjournals.jbchem.a131108.

33. Kobayashi S, Kainuma K, Suzuki S. Purification and some properties of Bacillus macerans cycloamylose (cyclodextrin) glucanotransferase. Carbohydr Res. 1978. V. 61. P. (229-238). doi: 10.1016/s0008-6215(00)84484- 5.

34. Li Y., Liu J., Wang Y., Liu B., Xie X., Jia R., Li C., Li Z. A two-stage temperature control strategy enhances extracellular secretion of recombinant αcyclodextrin glucosyltransferase in Escherichia coli. AMB Express. 2017. V.7(1). P.165. doi: 10.1186/s13568-017-0465-3.

35. Li Z., Ban X., Gu Z., Li C., Huang M., Hong Y., Cheng L. Mutations enhance β-cyclodextrin specificity of cyclodextrin glycosyltransferase from Bacillus circulans. Carbohydr Polym. 2014. V.108. P. 112-117. doi: 10.1016/j.carbpol.2014.03.015.

36. Li Z., Huang M., Gu Z., Holler T.P., Cheng L., Hong Y., Li C.. Asp577 mutations enhance the catalytic efficiency of cyclodextrin glycosyltransferase from Bacillus circulans. Int J Biol Macromol. 2016. V.83. P.111-116. doi: 10.1016/j.ijbiomac.2015.11.042.

37. Li Z., Wang M., Wang F., Gu Z., Du G., Wu J. Chen J. Gamma-Cyclodextrin: a review on enzymatic production and applications. Appl Microbiol Biotechnol. 2007. V.77(2). P.245-55. doi: 10.1007/s00253-007-1166-7.

38. Mahmud H., Ismail A., Abdul Rahim R., Low K.O., Md Illias R. Enhanced secretion of cyclodextrin glucanotransferase (CGTase) by Lactococcus lactis using heterologous signal peptides and optimization of cultivation conditions. J Biotechnol. 2019. V.296. P.22-31. doi: 10.1016/j.jbiotec.2019.02.013.

39. Makela M., Mattsson P., Schinina M.E., Korpela T. Purification and properties of cyclomaltodextrin glucanotransferase from an alkalophilic Bacillus sp. 7-12. Biotechn. Appl. Biochem. 1988. V. 10. P. 414-427. doi: 10.1111/j.1745-4514.2004.04603.x

40. Melzer S., Sonnendecker C., Föllner C., Zimmermann W. Stepwise error-prone PCR and DNA shuffling changed the pH activity range and product specificity of the cyclodextrin glucanotransferase from an alkaliphilic Bacillus sp. FEBS Open Bio. 2015. V.11(5). P. 528-34. doi: 10.1016/j.fob.2015.06.002.

41. Nik-Pa N. I. M., Sobri M.F.M., Abd-Aziz S., Ibrahim M.F., Bahrin E.K., Alitheen N. B. M., Ramli N. Combined Optimization of Codon Usage and Glycine Supplementation Enhances the Extracellular Production of a β-Cyclodextrin Glycosyltransferase from Bacillus sp. NR5 UPM in Escherichia coli. Int J Mol Sci. 2020. V.21(11). P.3919. doi: 10.3390/ijms21113919.

42. Schardinger F. Bildung kristallisierter polysaccharide (dextrine) aus särkekleister durch mikrobien. Centralbl. Bakteriol. Parasitenkd. Infektionskrankh. Hyg. Abt. II. 1911. V.29. P.188–197.

43. Schardinger F. Mitteilung aus der staatlichen untersuchungsanstalt für lebensmittel in Wien Azetorgärung. Wien. Klin. Wochenschr. 1904. V.17. P. 207–209

44. Schardinger F. Über thermophile Bakterien aus verschiedenen Speisen und Milch. Zeitschr. f. Untersuchung d. Nahr.-u. Genußmittel. 1903. V.6. P. 865–880. doi: 10.1007/BF02067497

45. Schmid G. Cyclodextrin glycosyltransferase production: yield enhancement by overexpression of cloned genes. Trends in Biotechnology. 1989. V.7(9). P. 244-248. doi: 10.1016/0167-7799(89)90015-2

46. Schwimmer S. Evidence for the purity of Schardinger dextrinogenase. Arch Biochem Biophys. 1953. V.43(1). P.108-117. doi: 10.1016/0003- 9861(53)90089-7.

47. Song B., Yue Y, Xie T., Qian S., Chao Y. Mutation of tyrosine167histidine at remote substrate binding subsite -6 in α-cyclodextrin glycosyltransferase enhancing α-cyclodextrin specificity by directed evolution. Mol Biotechnol. 2014. V.56(3). P.232-239. doi: 10.1007/s12033-013-9699-8.

48. Song K., Sun J., Wang W., Hao J. Heterologous Expression of Cyclodextrin Glycosyltransferase my20 in Escherichia coli and Its Application in 2-O-α-DGlucopyranosyl-L-Ascorbic Acid Production. Front Microbiol. 2021. V.12. P.664339. doi: 10.3389/fmicb.2021.664339.

49. Sonnendecker C., Melzer S., Zimmermann W. Engineered cyclodextrin glucanotransferases from Bacillus sp. G-825-6 produce large-ring cyclodextrins with high specificity. MicrobiologyOpen. 2019. V.8(6). e00757. doi: 10.1002/mbo3.757.

50. Sonnendecker C., Wei R., Kurze E., Wang J., Oeser T., Zimmermann W. Efficient extracellular recombinant production and purification of a Bacillus cyclodextrin glucanotransferase in Escherichia coli. Microb Cell Fact. 2017. V.16(1). P.87. doi: 10.1186/s12934-017-0701-1.

51. Sonnendecker C., Zimmermann W. Domain shuffling of cyclodextrin glucanotransferases for tailored product specificity and thermal stability. FEBS Open Bio. 2019. V.9(2). P.384-395. doi: 10.1002/2211-5463.12588.

52. Su L., Li Y., Wu J. Efficient secretory expression of Bacillus stearothermophilus α/β-cyclodextrin glycosyltransferase in Bacillus subtilis. J Biotechnol. 2021. V.331. P.74-82. doi: 10.1016/j.jbiotec.2021.03.011.

53. Takano T., Fukuda M., Monma M., Kobayashi S., Kainuma K., Yamane K. Molecular cloning, DNA nucleotide sequencing, and expression in Bacillus subtilis cells of the Bacillus macerans cyclodextrin glucanotransferase gene. J. Bacteriol. 1986. V.166(3). P.1118-1122. doi: 10.1128/jb.166.3.1118-1122.1986

54. Tao X., Su L, Wang L., Chen X., Wu J. Improved production of cyclodextrin glycosyltransferase from Bacillus stearothermophilus NO2 in Escherichia coli via directed evolution. Appl Microbiol Biotechnol. 2020. V.104(1). P.173-185. doi: 10.1007/s00253-019-10249-8.

55. Thoma J.A., Dygert S., Hsue K. A simple and specific assay for cyclodextrin transglucosidase. Analytical Biochemistry. 1965. V. 13(1). P.91-99. doi: 10.1016/0003-2697(65)90122-3

56. Tilden E.B., Adams M., Hudson C.S. Purification of the Amylase of Bacillus macerans. J. Am. Chem. Soc. 1942. V.64(6). P.1432–1433. doi: 10.1021/ja01258a052

57. Tilden E.B., Hudson C.S. Preparation and Properties of the Amylases Produced by Bacillus macerans and Bacillus polymyxa. J Bacteriol. 1942. V.43(4). P.527-544. doi: 10.1128/jb.43.4.527-544.1942.

58. Vakhitov V.A., Ahmetzjanov A.A., Bikbulatova S.M., Usanov N.G., Chemeris A.V. Molekuljarnoe klonirovanie, opredelenie nukleotidnoj posledovatel'nosti gena beta-ciklodekstringljukanotransferazy Bacillus sp. shtamma 6.6.3. i ee sravnitel'nyj analiz. Biotehnologija. 1999. No.1. P. 3-10. [Molecular cloning, determination of the nucleotide sequence of the gene -cyclodextringlucanotransferase Bacillus sp. strain 6.6.3. and its comparative analysis] (In Russian)

59. Villiers A. Sur la transformation de la fécule en dextrine par le ferment butyrique. Compt. Rendu. 1891. V.112. P. 435-438.

60. Wang H., Zhou W., Li H., Bu R. Optimization of the fermentation conditions for the mutant strain of βcyclodextrin glycosyltransferase H167C to produce cyclodextrins. Biotech. 2018. V.8(3). P.165. doi: 10.1007/s13205-018-1182-6.

61. Wang H., Zhou W., Li H., Rie B., Piao C. Improved activity of β-cyclodextrin glycosyltransferase from Bacillus sp. N-227 via mutagenesis of the conserved residues. Biotech. 2017. V.7(2). P.149. doi: 10.1007/s13205-017-0725-6.

62. Wang L., Chen S., Wu J. Cyclodextrin enhanced the soluble expression of Bacillus clarkii γ-CGTase in Escherichia coli. BMC Biotechnol. 2018. V.18(1). P.72. doi: 10.1186/s12896-018-0480-8. 

63. Wang L., Xia Y., Su L., Wu J. Modification of Bacillus clarkii γ-Cyclodextrin Glycosyltransferase and Addition of Complexing Agents to Increase γCyclodextrin Production. Journal of Agricultural and Food Chemistry. 2020. V.68(43). P.12079-12085. doi: 10.1021/acs.jafc.0c05408

64. Xie T., Hou Y., Li D., Yue Y., Qian S., Chao Y. Structural basis of a mutant Y195I α-cyclodextrin glycosyltransferase with switched product specificity from α-cyclodextrin to β-/γ-cyclodextrin. J Biotechnol. 2014. V.20(182-183). P. 92-96. doi: 10.1016/j.jbiotec.2014.03.014.

65. Xie T., Song B., Yue Y., Chao Y., Qian S. Sitesaturation mutagenesis of central tyrosine 195 leading to diverse product specificities of an α-cyclodextrin glycosyltransferase from Paenibacillus sp. 602-1. J Biotechnol. 2014. V. 20(170). P.10-16. doi: 10.1016/j.jbiotec.2013.10.032.

66. Yang L., Jia L., Yinglan W., Bingjie L., Xiaofang X., Rui J., Caiming L., Zhaofeng L. A two-stage temperature control strategy enhances extracellular secretion of recombinant α-cyclodextrin glucosyltransferase in Escherichia coli. AMB Express. 2017. V.7(1). P.165. doi: 10.1186/s13568-017-0465-3.

67. Zhang J., Zhang Y., Li M. High-level secretion and characterization of cyclodextrin glycosyltransferase in recombinant Komagataella phaffii. J Biotechnol. 2017b. V.259. P.126-134. doi: 10.1016/j.jbiotec.2017.07.031.

68. Zhang J., Zhao Y., Li M., Liu T. Optimization of defined medium for recombinant Komagataella phaffii expressing cyclodextrin glycosyltransferase. Biotechnol Prog. 2019. V35(5). e2867. doi: 10.1002/btpr.2867.

69. Zhang K., Su L., Duan X., Liu L., Wu J. Highlevel extracellular protein production in Bacillus subtilis using an optimized dual-promoter expression system. Microb Cell Fact. 2017a. V.16(1). P.32. doi: 10.1186/s12934-017-0649-1.

70. Zheng J., Li X., Wu H. High-level extracellular secretion and characterization of the thermophilic βcyclodextrin glucanotranferase from Paenibacillus campinasensis in Escherichia coli. Biotech. 2019. V.9(10). P.372. doi: 10.1007/s13205-019-1909-z