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Strategies for the Manipulation of Carbocations by Aristolochene Synthase

  • David J. Miller
  • Rudolf K. Allemann
Chapter

Abstract

Aristolochene synthase is a sesquiterpene cyclase that catalyses the high-precision conversion of farnesyl diphosphate to the sesquiterpene (+)-aristolochene via a tightly chaperoned carbocationic reaction cascade. This article examines recent work focussed on understanding the role this and other related enzymes play in controlling this chemistry. Through the use of X-ray crystallography, site-directed mutagenesis and substrate analogues, a better picture of how such proteins manipulate carbocations to arrive at specific hydrocarbon products is emerging.

Keywords

Terpenes Aristolochene synthase Farnesyl diphosphate Inhibition Carbocation Template 

Notes

Acknowledgements

The authors would like to acknowledge the many contributions made by the members of the Allemann group. This work was supported by the UK’s Biotechnology and Biological Sciences Research Council through research grants 6/B17177, BBS/Q/Q/2004/05499 and BB/G003572/1, the Engineering and Physical Sciences Research Council through grant EP/D06958/1, the Royal Society (grant 2007R2) and Cardiff University. We are grateful to Neil Young for preparing Figs. 12.4 and 12.6.

References

  1. Aaron JA, Lin X, Cane DE, Christianson DW (2010) Structure of epi-isozizaene synthase from Streptomyces coelicolor A3(2), a platform for new terpenoid cyclization templates. Biochemistry 49:1787–1797PubMedCrossRefGoogle Scholar
  2. Allemann RK, Young NJ, Ma S, Truhlar DG, Gao J (2007) Synthetic efficiency in enzyme mechanisms involving carbocations: aristolochene synthase. J Am Chem Soc 129:13008–13013PubMedCrossRefGoogle Scholar
  3. Banks RE, Tatlow JC (1986) A guide to modern organofluorine chemistry. J Fluor Chem 33:227–284CrossRefGoogle Scholar
  4. Calvert MJ, Ashton PR, Allemann RK (2002a) Germacrene A is a product of the aristolochene synthase-mediated conversion of farnesylpyrophosphate to aristolochene. J Am Chem Soc 124:11636–11641PubMedCrossRefGoogle Scholar
  5. Calvert MJ, Taylor SE, Allemann RK (2002) Tyrosine 92 of aristolochene synthase directs cyclisation of farnesyl pyrophosphate. Chem Commun 2384–2385Google Scholar
  6. Cane DE (1990) The enzymatic formation of sesquiterpenes. Chem Rev 90:1089–1093CrossRefGoogle Scholar
  7. Cane DE, Bryant C (1994) Aristolochene synthase. Mechanism-based inhibition of a terpenoid cyclase. J Am Chem Soc 116:12063–12064CrossRefGoogle Scholar
  8. Cane DE, Tsantrizos YS (1996) Aristolochene synthase. Elucidation of the cryptic Germacrene A synthase activity using the anomalous substrate dihydrofarnesyl diphosphate. J Am Chem Soc 118:10037–10040CrossRefGoogle Scholar
  9. Cane DE, Prabhakaran PC, Salaski EJ, Harrison PHM, Noguchi H, Rawlings BJ (1989) Aristolochene biosynthesis and enzymatic cyclization of farnesyl pyrophosphate. J Am Chem Soc 111:8914–8916CrossRefGoogle Scholar
  10. Cane DE, Prabhakaran PC, Oliver JS, McIlwaine DB (1990a) Aristolochene biosynthesis. Stereochemistry of the deprotonation steps in the enzymatic cyclization of farnesyl pyrophosphate. J Am Chem Soc 112: 3209–3210CrossRefGoogle Scholar
  11. Cane DE, Prabhakaran PC, Oliver JS, McIlwaine DB (1990b) Aristolochene biosynthesis. Stereochemistry of the deprotonation steps in the enzymatic cyclization of farnesyl pyrophosphate. J Am Chem Soc 112: 3209–3210CrossRefGoogle Scholar
  12. Caruthers JM, Kang I, Rynkiewicz MJ, Cane DE, Christianson DW (2000) Crystal structure determination of aristolochene synthase from the blue cheese mold, Penicillium roqueforti. J Biol Chem 275: 25533–25539PubMedCrossRefGoogle Scholar
  13. Christianson DW (2006) Structural biology and chemistry of the terpenoid cyclases. Chem Rev 106:3412–3442PubMedCrossRefGoogle Scholar
  14. Deligeorgopoulou A, Allemann RK (2003) Evidence for differential folding of farnesyl pyrophosphate in the active site of aristolochene synthase: a single-point mutation converts aristolochene synthase into an (E)-β-farnesene synthase. Biochemistry 42:7741–7747PubMedCrossRefGoogle Scholar
  15. Deligeorgopoulou A, Taylor SE, Forcat S, Allemann RK (2003) Stabilisation of eudesmane cation by tryptophan 334 during aristolochene synthase catalysis. Chem Commun 2162–2163Google Scholar
  16. Dougherty DA (1996) Cation-π interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271:163–168PubMedCrossRefGoogle Scholar
  17. Faraldos JA, Allemann RK (2011) Inhibition of (+)-aristolochene synthase with iminium salts resembling eudesmane cation. Org Lett 13:1202–1205PubMedCrossRefGoogle Scholar
  18. Faraldos JA, Gonzalez V, Senske M, Allemann RK (2011) Templating effects in aristolochene synthase catalysis: elimination versus cyclisation. Org Biomol Chem 9. 6920–9623Google Scholar
  19. Faraldos JA, Antonczak AK, González VG, Fullerton R, Tippmann EM, Allemann RK (2011) Probing eudesmane cation−π Interactions in catalysis by aristolochene synthase with non-canonical amino acids. J Am Chem Soc 133:13906–13909Google Scholar
  20. Forcat S, Allemann RK (2004) Dual role for phenylalanine 178 during catalysis by aristolochene synthase. Chem Commun 2094–2095Google Scholar
  21. Forcat S, Allemann RK (2006) Stabilisation of transition states prior to and following eudesmane cation in aristolochene synthase. Org Biomol Chem 4:2563–2567PubMedCrossRefGoogle Scholar
  22. Gennadios HA, Gonzalez V, Di Costanzo L, Li AA, Yu FL, Miller DJ, Allemann RK, Christianson DW (2009) Crystal structure of (+)-δ-cadinene synthase from Gossypium arboreum and evolutionary divergence of metal binding motifs for catalysis. Biochemistry 48:6175–6183PubMedCrossRefGoogle Scholar
  23. Glasby JS (1982) Encyclopedia of Terpenoids. Wiley, ChichesterGoogle Scholar
  24. Greenhagen BT, O’Maille PE, Noel JP, Chappell J (2006) Identifying and manipulating structural determinates linking catalytic specificities in terpene synthases. Proc Natl Acad Sci USA 103:9826–9831PubMedCrossRefGoogle Scholar
  25. Hyatt DC, Youn B, Zhao Y, Santhamma B, Coates RM, Croteau RB, Kang C (2007) Structure of limonene synthase, a simple model for terpenoid cyclase catalysis. Proc Natl Acad Sci USA 104:5360–5365PubMedCrossRefGoogle Scholar
  26. Jin Y, Williams DC, Croteau R, Coates RM (2005) Taxadiene synthase-catalyzed cyclization of 6-fluorogeranylgeranyl diphosphate to 7-fluoroverticillenes. J Am Chem Soc 127:7834–7842PubMedCrossRefGoogle Scholar
  27. Köksal M, Zimmer I, Schnitzler JP, Christianson DW (2010) Structure of isoprene synthase illuminates the chemical mechanism of teragram atmospheric carbon emission. J Mol Biol 402:363–373PubMedCrossRefGoogle Scholar
  28. Köksal M, Hu HY, Coates RM, Peters RJ, Christianson DW (2011a) Structure and mechanism of the diterpene cyclase ent-copalyl diphosphate synthase. Nat Chem Biol 7:431–433PubMedCrossRefGoogle Scholar
  29. Köksal M, Jin YH, Coates RM, Croteau R, Christianson DW (2011b) Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 469:116–120PubMedCrossRefGoogle Scholar
  30. Lesburg CA, Zhai G, Cane DE, Christianson DW (1997) Crystal structure of pentalenene synthase: mechanistic insights on terpenoid cyclization reactions in biology. Science 277:1820–1824PubMedCrossRefGoogle Scholar
  31. Ma JC, Dougherty DA (1997) The cation-π interaction. Chem Rev 97:1303–1324PubMedCrossRefGoogle Scholar
  32. Mann FM, Prisic S, Hu HY, Xu MM, Coates RM, Peters RJ (2009) Characterization and inhibition of a class II diterpene cyclase from Mycobacterium tuberculosis: implications for tuberculosis. J Biol Chem 284:23574–23579PubMedCrossRefGoogle Scholar
  33. McGeady P, Pyun HJ, Coates RM, Croteau R (1992) Biosynthesis of monoterpenes: Inhibition of (+)-pinene and (-)-pinene cyclases by thia and aza analogs of the 4R- and 4S-α-terpinyl carbocation. Arch Biochem Biophys 299:63–72PubMedCrossRefGoogle Scholar
  34. Miller DJ, Yu F, Young NJ, Allemann RK (2007a) Competitive inhibition of aristolochene synthase by phenyl-substituted farnesyl diphosphates: evidence of active site plasticity. Org Biomol Chem 5:3287–3298PubMedCrossRefGoogle Scholar
  35. Miller DJ, Yu F, Allemann RK (2007b) Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. ChemBioChem 8:1819–1825PubMedCrossRefGoogle Scholar
  36. Miller DJ, Gao J, Truhlar DG, Young NJ, Gonzalez V, Allemann RK (2008) Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti. Org Biomol Chem 6:2346–2354PubMedCrossRefGoogle Scholar
  37. O’Maille PE, Chappell J, Noel JP (2006) Biosynthetic potential of sesquiterpene synthases: alternative products of tobacco 5-epi-aristolochene synthase. Arch Biochem Biophys 448:73–82PubMedCrossRefGoogle Scholar
  38. Peters RJ, Ravn MM, Coates RM, Croteau RB (2001) Bifunctional abietadiene synthase: free diffusive transfer of the (+)-copalyl diphosphate intermediate between two distinct active sites. J Am Chem Soc 123: 8974–8978PubMedCrossRefGoogle Scholar
  39. Ravn MM, Peters RJ, Coates RM, Croteau R (2002) Mechanism of abietadiene synthase catalysis: stereochemistry and stabilization of the cryptic pimarenyl carbocation intermediates. J Am Chem Soc 124:6998–7006PubMedCrossRefGoogle Scholar
  40. Roy A, Roberts FG, Wilderman PR, Zhou K, Peters RJ, Coates RM (2007) 16-Aza-ent-beyerane and 16-Aza-ent-trachylobane: potent mechanism-based inhibitors of recombinant ent-kaurene synthase from Arabidopsis thaliana. J Am Chem Soc 129:12453–12460PubMedCrossRefGoogle Scholar
  41. Rynkiewicz MJ, Cane DE, Christianson DW (2001) Structure of trichodiene synthase from Fusarium sporotrichioides provides mechanistic inferences on the terpene cyclization cascade. Proc Natl Acad Sci USA 98:13543–13548PubMedCrossRefGoogle Scholar
  42. Shishova EY, Di Costanzo L, Cane DE, Christianson DW (2007) X-ray crystal structure of aristolochene synthase from Aspergillus terreus and evolution of templates for the cyclization of farnesyl diphosphate. Biochemistry 46:1941–1951PubMedCrossRefGoogle Scholar
  43. Shishova EY, Yu F, Miller DJ, Faraldos JA, Zhao YX, Coates RM, Allemann RK, Cane DE, Christianson DW (2008) X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis. J Biol Chem 283:15431–15439PubMedCrossRefGoogle Scholar
  44. Starks CM, Back K, Chappell J, Noel JP (1997) Structural basis for cyclic terpene biosynthesis by tobacco 5-epi-aristolochene synthase. Science 277:1815–1820PubMedCrossRefGoogle Scholar
  45. Thulasiram HV, Erickson HK, Poulter CD (2007) Chimeras of two isoprenoid synthases catalyze all four coupling reactions in isoprenoid biosynthesis. Science 316:73–76PubMedCrossRefGoogle Scholar
  46. Thulasiram HV, Erickson HK, Poulter CD (2008) A common mechanism for branching, cyclopropanation, and cyclobutanation reactions in the isoprenoid biosynthetic pathway. J Am Chem Soc 130:1966–1971PubMedCrossRefGoogle Scholar
  47. Vedula LS, Cane DE, Christianson DW (2005) Role of arginine-304 in the diphosphate-triggered active site closure mechanism of trichodiene synthase. Biochemistry 44:12719–12727PubMedCrossRefGoogle Scholar
  48. Vedula LS, Zhao YX, Coates RM, Koyama T, Cane DE, Christianson DW (2007) Exploring biosynthetic diversity with trichodiene synthase. Arch Biochem Biophys 466:260–266PubMedCrossRefGoogle Scholar
  49. Wei RD, Schnoes HK, Hart PA, Strong FM (1975) The structure of PR toxin, a mycotoxin from Penicillium roqueforti. Tetrahedron 31:109–114CrossRefGoogle Scholar
  50. Whittington DA, Wise ML, Urbansky M, Coates RM, Croteau RB, Christianson DW (2002) Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase. Proc Natl Acad Sci USA 99:15375–15380PubMedCrossRefGoogle Scholar
  51. Yoshikuni Y, Ferrin TE, Keasling JD (2006a) Designed divergent evolution of enzyme function. Nature 440:1078–1082PubMedCrossRefGoogle Scholar
  52. Yoshikuni Y, Martin VJJ, Ferrin TE, Keasling JD (2006b) Engineering cotton (+)-δ-cadinene synthase to an altered function: germacrene D-4-ol synthase. Chem Biol 13:91–98PubMedCrossRefGoogle Scholar
  53. Yu F, Miller DJ, Allemann RK (2007) Probing the reaction mechanism of aristolochene synthase with 12,13-difluorofarnesyl diphosphate. Chem Commun 4155–4157Google Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.School of Chemistry & Cardiff Catalysis InstituteCardiff UniversityCardiffUK

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