Synlett 2014; 25(6): 766-782
DOI: 10.1055/s-0033-1340624
account
© Georg Thieme Verlag Stuttgart · New York

Microbial Terpenes: A Perspective on Their Chemistry and Biosynthesis

Christian A. Citron
Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany   Fax: +49(531)3915264   Email: j.dickschat@tu-braunschweig.de
,
Jeroen S. Dickschat*
Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany   Fax: +49(531)3915264   Email: j.dickschat@tu-braunschweig.de
› Author Affiliations
Further Information

Publication History

Received: 01 November 2013

Accepted after revision: 04 December 2013

Publication Date:
10 February 2014 (online)


Abstract

This personal account summarizes our ongoing work on the bioorganic chemistry of diverse microbial terpenoids. First, two selected total syntheses that were recently completed in our group are presented. We then show how the fundamental technique for our analytical work, closed-loop stripping apparatus (CLSA) in combination with gas chromatography/mass spectrometry (GC/MS), can be used to efficiently identify volatile natural products from various bacteria and fungi. The largest compound class among these volatiles is the terpenes. The CLSA technique can also be successfully applied to study interesting problems of the sometimes puzzling biosynthetic pathways towards terpenes. For this purpose we have developed two new CLSA-based methods, the first using 13C-labeled precursors in feeding studies which allow for structure elucidations of microgram amounts of terpenes in complex headspace mixtures, and the second, a genome-mining approach via heterologous expression for the rapid chemical characterization of bacterial terpene cyclases. Recent developments in our laboratory include mechanistic investigations based on enzyme structural data in combination with site-specific mutations of terpene cyclases.

1 Introduction

2 Total Synthesis of Glaciapyrrole A and Tricho-acorenol

3 Feeding Experiments with Deuterated Precursors

4 The IspH Reaction

5 Feeding Experiments with 13C-Labeled Precursors

6 Genome Mining and Closed-Loop Stripping Apparatus

7 Conclusion

 
  • References

  • 1 Dickschat JS. Nat. Prod. Rep. 2010; 27: 343
  • 2 von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D. Angew. Chem. Int. Ed. 2006; 45: 5072
  • 3 Hider RC, Kong X. Nat. Prod. Rep. 2010; 27: 637
  • 4 Hertweck C. Angew. Chem. Int. Ed. 2009; 48: 4688
  • 5 McGuire JM, Bunch RL, Anderson RC, Boaz HE, Flynn EH, Powell HM, Smith JW. Antibiot. Chemother. 1952; 2: 281
  • 6 Harris DR, McGeachin SG, Mills HH. Tetrahedron Lett. 1965; 6: 679
  • 7 Cortes J, Haydock SF, Roberts GA, Bevitt DJ, Leadlay PF. Nature 1990; 348: 176
  • 8 Jing-Ming L, Mu-Yun N, Ju-Fen F, You-You T, Zhao-Hua W, Yu-Lin W, Wei-Shan C. Acta Chim. Sinica 1979; 37: 129
  • 9 Desjardins RE, Canfield CJ, Haynes JD, Chulay JD. Antimicrob. Agents Chemother. 1979; 16: 710
  • 10 Enserink M. Science 2005; 307: 33
  • 11 Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MC. Y, Withers ST, Shiba Y, Sarpong R, Keasling JD. Nature 2006; 440: 940
  • 12 Lévesque F, Seeberger PH. Angew. Chem. Int. Ed. 2012; 51: 1706
  • 13 Fleming A. Br. J. Exp. Pathol. 1929; 10: 226
  • 14 Schulz S, Dickschat JS. Nat. Prod. Rep. 2007; 24: 814
  • 15 Gerber NN, Chevalier HA. Appl. Microbiol. 1965; 13: 935
  • 16 Young WF, Horth H, Crane R, Odgen T, Arnott M. Water Res. 1996; 30: 331
  • 17 Gerber NN. J. Antibiot. 1969; 22: 508
  • 18 Izaguirre G, Hwang CJ, Krasner SW, McGuire MJ. Appl. Environ. Microbiol. 1982; 43: 708
  • 19 Zhao B, Lin X, Lei L, Lamb DC, Kelly SL, Waterman MR, Cane DE. J. Biol. Chem. 2008; 283: 8183
  • 20 Takamatsu S, Lin X, Nara A, Komatsu M, Cane DE, Ikeda H. Microb. Biotechnol. 2011; 4: 184
  • 21 Grob K, Grob KJr, Grob G. J. Chromatogr., A 1975; 106: 299
  • 22 Dickschat JS, Wenzel SC, Bode HB, Müller R, Schulz S. ChemBioChem 2004; 5: 778
  • 23 Joulain D, König WA. The Atlas of Spectral Data of Sesquiterpene Hydrocarbons 1998;
  • 24 Adams RP. Identification of Essential Oil Components by Gas Chromatography/Mass Spectrometry. Allured; Carol Stream, IL: 2009
  • 25 van den Dool H, Kratz Dec P. J. Chromatogr., A 1963; 11: 463
  • 26 Dickschat JS, Zell C, Brock NL. ChemBioChem 2010; 11: 417
  • 27 Liu Y, Zhang S, Abreu PJ. M. Nat. Prod. Rep. 2006; 23: 630
  • 28 Macherla VR, Liu J, Bellows C, Teisan S, Nicholson B, Lam KS, Botts BC. M. J. Nat. Prod. 2005; 68: 780
  • 29 Rîclea R, Dickschat JS. Chem. Eur. J. 2011; 17: 11930
  • 30 Roth S, Göhler S, Cheng H, Stark CB. W. Eur. J. Org. Chem. 2005; 4109
  • 31 Corey EJ, Cho H, Rücker C, Hua DH. Tetrahedron Lett. 1981; 22: 3455
  • 32 Mata EG, Thomas EJ. J. Chem. Soc., Perkin Trans. 1 1995; 785
  • 33 Nicolaou KC, Claremon DA, Papahatjis DP. Tetrahedron Lett. 1981; 22: 4647
  • 34 Sharma GV. M, Srinivas B, Krishna PR. Tetrahedron Lett. 2003; 44: 4689
  • 35 Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless KB. J. Am. Chem. Soc. 1987; 109: 5765
  • 36 Taber DF, Bhamidipati RS, Thomas ML. J. Org. Chem. 1994; 59: 3442
  • 37 Hoye TR, Ye Z. J. Am. Chem. Soc. 1996; 118: 1801
  • 38 Makabe H, Tanimoto H, Tanaka A, Oritani T. Heterocycles 1996; 43: 2229
  • 39 Hattori Y, Kimura Y, Moroda A, Konno H, Abe M, Miyoshi H, Goto T, Makabe H. Chem. Asian J. 2006; 1: 894
  • 40 Brock NL, Dickschat JS. Eur. J. Org. Chem. 2011; 5167
  • 41 Lange GL, Orrom WJ, Wallace DJ. Tetrahedron Lett. 1977; 18: 4479
  • 42 Pesaro M, Bachmann J.-P. J. Chem. Soc., Chem. Commun. 1978; 203
  • 43 Baldwin SW, Fredericks JE. Tetrahedron Lett. 1982; 23: 1235
  • 44 Harman GE, Howell CR, Viterbo A, Chet I, Lorito M. Nat. Rev. Microbiol. 2004; 2: 43
  • 45 Harman GE. Phytopathology 2006; 96: 190
  • 46 Garo E, Starks CM, Jensen PR, Fenical W, Lobkovsky E, Clardy J. J. Nat. Prod. 2003; 66: 423
  • 47 Quian-Cutrone J, Huang S, Chang LP, Pirnik DM, Klohr SE, Dalterio RA, Hugill R, Lowe S, Alam M, Kardow KF. J. Antibiot. 1996; 49: 990
  • 48 Bamburg JR, Strong FM. Phytochemistry 1969; 8: 2405
  • 49 Wolinsky J, Wolf H, Gibson T. J. Org. Chem. 1963; 28: 274
  • 50 Wolinsky J, Chan D. J. Org. Chem. 1965; 30: 41
  • 51 Krasovskiy A, Kopp F, Knochel P. Angew. Chem. Int. Ed. 2006; 45: 497
  • 52 Huang Q, Tezuka Y, Hatanaka Y, Kikuchi T, Nishi A, Tubaki K. Chem. Pharm. Bull. 1995; 43: 1035
  • 53 Dickschat JS, Citron CA, Brock NL, Rîclea R, Kuhz H. Eur. J. Org. Chem. 2011; 3339
  • 54 Zamir LO, Nguyen C.-D. J. Labelled Compd. Radiopharm. 1987; 24: 1461
  • 55 Zamir LO, Nguyen C.-D. J. Labelled Compd. Radiopharm. 1988; 25: 1189
  • 56 Citron CA, Rîclea R, Brock NL, Dickschat JS. RSC Adv. 2011; 1: 290
  • 57 Ganem B, Dong Y, Zheng YF, Prestwich GD. J. Org. Chem. 1999; 64: 5441
  • 58 Cornforth JW, Cornforth RH, Popjak G, Yengoyan L. J. Biol. Chem. 1966; 241: 3970
  • 59 Dickschat JS. Nat. Prod. Rep. 2011; 28: 1917
  • 60 Citron CA, Dickschat JS. Org. Biomol. Chem. 2013; 11: 7447
  • 61 McCapra F, Scott AI, Sim GA, Young DW. Proc. Chem. Soc., London 1962; 185
  • 62 Bömke C, Tudzynski B. Phytochemistry 2009; 70: 1876
  • 63 Davidson SE, Reid JB, Halliwell CA. Phytochem. Rev. 2006; 6: 405
  • 64 Hedden P, Phillips AL, Rojas MC, Carrera E, Tudzynski B. J. Plant Growth Regul. 2002; 20: 319
  • 65 MacMillan J. J. Plant Growth Regul. 2002; 20: 387
  • 66 Seto F. Ann. Phytopathol. Soc. Jap. 1928; 2: 118
  • 67 Springer JP, Clardy J, Cole RJ, Kirksey JW, Hill RK, Carlson RM, Isidor JL. J. Am. Chem. Soc. 1974; 96: 2267
  • 68 Bacon CW, Porter JK, Norred WP, Leslie JF. Appl. Environ. Microbiol. 1996; 62: 4039
  • 69 Kjær D, Kjær A, Pederson C, Bu’Lock JD, Smith JR. J. Chem. Soc. C 1971; 2792
  • 70 Ueno Y, Hosoya M, Ishikawa Y. J. Biochem. 1969; 66: 419
  • 71 Yoshizawa T. Mycotoxins 2003; 53: 113
  • 72 Avalos J, Cerda-Olmedo E. Phytochemistry 1986; 25: 1837
  • 73 Barrero AF, Sanchez JF, Oltra JE, Tamayo N, Cerda-Olmedo E, Candau R, Avalos J. Phytochemistry 1991; 30: 2259
  • 74 Rojas MC, Hedden P, Gaskin P, Tudzynski B. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 5838
  • 75 Malonek S, Rojas MC, Hedden P, Gaskin P, Hopkins P, Tudzynski B. Appl. Environ. Microbiol. 2005; 71: 1462
  • 76 Tudzynski B, Rojas MC, Gaskin P, Hedden P. J. Biol. Chem. 2002; 277: 21246
  • 77 Tudzynski B, Mihlan M, Rojas MC, Linnemannstöns P, Gaskin P, Hedden P. J. Biol. Chem. 2003; 278: 28635
  • 78 Bhattacharya A, Kourmpetli S, Ward DA, Thomas SG, Gong F, Powers FJ, Carrera E, Taylor B, de Caceres Gonzalez FN, Tudzynski B, Phillips AL, Davey MR, Hedden P. Plant Physiol. 2012; 160: 837
  • 79 Kimura M, Tokai T, Takahashi-Ando N, Ohsato S, Fujimura M. Biosci. Biotechnol. Biochem. 2007; 71: 2105
  • 80 Nozoe S, Machida Y. Tetrahedron Lett. 1970; 11: 2671
  • 81 Hohn TM, Vanmiddlesworth F. Arch. Biochem. Biophys. 1986; 251: 756
  • 82 Dickschat JS, Brock NL, Citron CA, Tudzynski B. ChemBioChem 2011; 12: 2088
  • 83 Cane DE, Ha H.-J. J. Am. Chem. Soc. 1986; 108: 3097
  • 84 Hong YJ, Tantillo DJ. Org. Lett. 2006; 8: 4601
  • 85 Brock NL, Tudzynski B, Dickschat JS. ChemBioChem 2011; 12: 2667
  • 86 Darken MA, Jensen AL, Shu P. Appl. Microbiol. 1959; 7: 301
  • 87 Sun TP, Kamiya Y. Plant Cell 1994; 6: 1509
  • 88 Yamaguchi S, Saito T, Abe H, Yamane H, Murofushi N, Kamiya Y. Plant J. 1996; 10: 203
  • 89 Morrone D, Chambers J, Lowry L, Kim G, Anterola A, Bender K, Peters RJ. FEBS Lett. 2009; 583: 475
  • 90 Tudzynski B, Kawaide H, Kamiya Y. Curr. Genet. 1998; 34: 234
  • 91 Peters RJ. Nat. Prod. Rep. 2010; 27: 1521
  • 92 Rohmer M. Nat. Prod. Rep. 1999; 16: 565
  • 93 Eisenreich W, Rohdich F, Bacher A. Trends Plant Sci. 2001; 6: 78
  • 94 Wiesner J, Hintz M, Altincicek B, Sanderbrand S, Weidemeyer C, Beck E, Jomaa H. Exp. Parasitol. 2000; 96: 182
  • 95 Cassera MB, Gozzo FC, D’Alexandri FL, Merino EF, del Portillo HA, Peres VJ, Almeida IC, Eberlin MN, Wunderlich G, Wiesner J, Jomaa H, Kimura EA, Katzin AM. J. Biol. Chem. 2004; 279: 51749
  • 96 Oldfield E. Acc. Chem. Res. 2010; 43: 1216
  • 97 Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Wiedemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E. Science 1999; 285: 1573
  • 98 Kuzuyama T, Takahashi S, Watanabe H, Seto H. Tetrahedron Lett. 1998; 39: 4509
  • 99 Kuzuyama T, Takagi M, Kaneda K, Dairi T, Seto H. Tetrahedron Lett. 2000; 41: 703
  • 100 Kuzuyama T, Takagi M, Kaneda K, Watanabe H, Dairi T, Seto H. Tetrahedron Lett. 2000; 41: 2925
  • 101 Takagi M, Kuzuyama T, Kaneda K, Watanabe H, Dairi T, Seto H. Tetrahedron Lett. 2000; 41: 3395
  • 102 Hecht S, Eisenreich W, Adam P, Amslinger S, Kis K, Bacher A, Arigoni D, Rohdich F. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 14837
  • 103 Rohdich F, Hecht S, Gärtner K, Adam P, Krieger C, Amslinger S, Arigoni D, Bacher A, Eisenreich W. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 1158
  • 104 Rohdich F, Zepeck F, Adam P, Hecht S, Kaiser J, Laupitz R, Gräwert T, Amslinger S, Eisenreich W, Bacher A, Arigoni D. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 1586
  • 105 Kollas A.-K, Duin EC, Eberl M, Altincicek B, Hintz M, Reichenberg A, Henschker D, Henne A, Steinbrecher I, Ostrovsky DN, Hedderich R, Beck E, Jomaa H, Wiesner J. FEBS Lett. 2002; 532: 432
  • 106 Seemann M, Tse Sum Bui B, Wolff M, Tritsch D, Campos N, Boronat A, Marquet A, Rohmer M. Angew. Chem. Int. Ed. 2002; 41: 4337
  • 107 Brandt W, Dessoy MA, Fulhorst M, Gao W, Zenk MH, Wessjohann LA. ChemBioChem 2004; 5: 311
  • 108 Nyland RL, Xiao Y, Liu P, Freel Meyers CL. J. Am. Chem. Soc. 2009; 131: 17734
  • 109 Xiao Y, Nyland RL, Freel Meyers CL, Liu P. Chem. Commun. 2010; 46: 7220
  • 110 Xiao Y, Rooker D, You Q, Freel Meyers CL, Liu P. ChemBioChem 2011; 12: 527
  • 111 Wang W, Li J, Huang C, Zhang Y, Oldfield E. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 11189
  • 112 Xiao Y, Zhao ZK, Liu P. J. Am. Chem. Soc. 2008; 130: 2164
  • 113 Xiao Y, Liu P. Angew. Chem. Int. Ed. 2008; 47: 9722
  • 114 Chang WC, Xiao Y, Liu HW, Liu P. Angew. Chem. Int. Ed. 2011; 50: 12304
  • 115 Wang W, Wang K, Liu Y.-L, No J.-H, Li J, Nilges MJ, Oldfield E. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 4522
  • 116 Altincicek B, Duin EC, Reichenberg A, Hedderich R, Kollas A.-K, Hintz M, Wagner S, Wiesner J, Beck E, Jomaa H. FEBS Lett. 2002; 532: 437
  • 117 Xiao Y, Chang WC, Liu HW, Liu P. Org. Lett. 2011; 13: 5912
  • 118 Proteau PJ, Woo Y.-H, Williamson RT, Phaosiri C. Org. Lett. 1999; 1: 921
  • 119 Cane DE, Abell C, Harrison PH. M, Hubbard BR, Kane CT, Lattman R, Oliver JS, Weiner SW. Philos. Trans. R. Soc. London, Ser. B 1991; 332: 123
  • 120 Giner J.-L. Tetrahedron Lett. 1998; 39: 2479
  • 121 Citron CA, Brock NL, Rabe P, Dickschat JS. Angew. Chem. Int. Ed. 2012; 51: 4053
  • 122 Span I, Gräwert T, Bacher A, Eisenreich W, Groll M. J. Mol. Biol. 2012; 416: 1
  • 123 Brock NL, Ravella SR, Schulz S, Dickschat JS. Angew. Chem. Int. Ed. 2013; 52: 2100
  • 124 Dickschat JS, Nawrath T, Thiel V, Kunze B, Müller R, Schulz S. Angew. Chem. Int. Ed. 2007; 46: 8287
  • 125 Komatsu M, Tsuda M, Omura S, Oikawa H, Ikeda H. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 7422
  • 126 Wang C.-M, Cane DE. J. Am. Chem. Soc. 2008; 130: 8908
  • 127 Chou WK. W, Ikeda H, Cane DE. Tetrahedron 2011; 67: 6627
  • 128 Köksal M, Chou WK. W, Cane DE, Christianson DW. Biochemistry 2012; 51: 3011
  • 129 Brock NL, Dickschat JS. ChemBioChem 2013; 14: 1189
  • 130 Hohn TM, Plattner RD. Arch. Biochem. Biophys. 1989; 272: 137
  • 131 Proctor RH, Hohn TM. J. Biol. Chem. 1993; 268: 4543
  • 132 Moreau S, Lablache-Combier A, Biguet J. Appl. Environ. Microbiol. 1980; 39: 770
  • 133 Hedden P. Physiol. Plant. 1997; 101: 709
  • 134 Castellaro SJ, Dolan SC, Hedden P, Gaskin P, Macmillan J. Phytochemistry 1990; 29: 1833
  • 135 Hanson JR, Hawker J, White AF. J. Chem. Soc., Perkin Trans. 1 1972; 1892
  • 136 Birch AJ, Richards RW, Smith H. Tetrahedron 1959; 7: 241
  • 137 Citron CA, Brock NL, Dickschat JS. Chem. Commun. 2014; doi: 10.1039/C3CC45982A
  • 138 Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ. Nucleic Acids Res. 1997; 25: 3389
  • 139 Citron CA, Gleitzmann J, Laurenzano G, Pukall R, Dickschat JS. ChemBioChem 2012; 13: 202
  • 140 Rabe P, Citron CA, Dickschat JS. ChemBioChem 2013; 14: 2345
  • 141 Cane DE, Sohng JK, Lamberson CR, Rudnicki SM, Wu Z, Lloyd MD, Oliver JS, Hubbard BR. Biochemistry 1994; 33: 5846
  • 142 Lin X, Hopson R, Cane DE. J. Am. Chem. Soc. 2006; 128: 6022
  • 143 Chou WK. W, Fanizza I, Uchiyama T, Komatsu M, Ikeda H, Cane DE. J. Am. Chem. Soc. 2010; 132: 8850
  • 144 Hu Y, Chou WK. W, Hopson R, Cane DE. Chem. Biol. 2011; 18: 32
  • 145 Nakano C, Kim MH.-K, Ohnishi Y. ChemBioChem 2011; 12: 1988
  • 146 Nakano C, Kim MH.-K, Ohnishi Y. ChemBioChem 2011; 12: 2403
  • 147 Nakano C, Horinouchi S, Ohnishi Y. J. Biol. Chem. 2011; 286: 27980
  • 148 Nakano C, Tezuka T, Horinouchi S, Ohnishi Y. J. Antibiot. 2012; 65: 551
  • 149 Nakano C, Kudo F, Eguchi T, Ohnishi Y. ChemBioChem 2011; 12: 2271
  • 150 Agger SA, Lopez-Gallego F, Hoye TR, Schmidt-Dannert C. J. Bacteriol. 2008; 190: 6084
  • 151 Cane DE, Watt RM. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 1547
  • 152 Cane DE, He X, Kobayashi Y, Omura S, Ikeda H. J. Antibiot. 2006; 59: 471
  • 153 Giglio S, Jiang J, Saint CP, Cane DE, Monis PT. Environ. Sci. Technol. 2008; 42: 8027
  • 154 Giglio S, Chou WK. W, Ikeda H, Cane DE, Monis PT. Environ. Sci. Technol. 2011; 45: 992
  • 155 Khorana HG, Agarwal KL, Büchi H, Caruthers MH, Gupta NK, Kleppe K, Kumar A, Ohtsuka E, Rajbhandary UL, van de Sande JH, Sgaramella V, Terao T, Weber H, Yamada T. J. Mol. Biol. 1972; 72: 209
  • 156 Itakaru K, Hirose T, Crea R, Riggs AD, Heyneker HL, Bolivar F, Boyer HW. Science 1977; 198: 1056
  • 157 Edge MD, Greene AR, Heathcliffe GR, Meacock PA, Schuch W, Scanlon DB, Atkinson TC, Newton CR, Markham AF. Nature 1981; 292: 756
  • 158 Rabe P, Dickschat JS. Angew. Chem. Int. Ed. 2013; 52: 1810
  • 159 Brock NL, Huss K, Tudzynski B, Dickschat JS. ChemBioChem 2013; 14: 311
  • 160 Wiemann P, Sieber CM. K, von Bargen KW, Studt L, Niehaus E.-M, Espino JJ, Huß K, Michielse CB, Albermann S, Wagner D, Bergner SV, Connolly LR, Fischer A, Reuter G, Kleigrewe K, Bald T, Wingfield BD, Ophir R, Freeman S, Hippler M, Smith KM, Brown DW, Proctor RH, Münsterkötter M, Freitag M, Humpf H.-U, Güldener U, Tudzynski B. PLoS Pathog. 2013; 9: e1003475
  • 161 Braun NA, Meier M, Kohlenberg B, Valder C, Neugebauer M. J. Essent. Oil Res. 2003; 15: 381
  • 162 Brock NL, Dickschat JS In Natural Products - Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes . Ramawat KG, Mérillon J.-M. Springer; Berlin: 2013. 1st ed., Vol. 4 2693
  • 163 Oldfield E, Lin F.-Y. Angew. Chem. Int. Ed. 2012; 51: 1124
  • 164 Baer P, Rabe P, Citron CA, de Oliveira Mann CC, Kaufmann N, Groll M, Dickschat JS. ChemBioChem 2014; 15: 213