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The cyanobacterial alkaloid nostocarboline: an inhibitor of acetylcholinesterase and trypsin

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Abstract

Preselected cyanobacterial strains (available from culture collections and our own isolates), belonging primarily to the heterocystous cluster, were screened for inhibitors against butyrylcholinesterase. About one-half of the extracts exhibited inhibitory activity. Nostocarboline, the responsible metabolite in Nostoc 78–12A, was studied in more detail as an acetylcholinesterase (AChE) inhibitor. The compound showed potent activity against this enzyme (IC50 = 5.3 µM), and the Michaelis-Menten kinetics indicated a non-competitive component in the inhibitory mechanism. In addition, nostocarboline turned out to be a potent inhibitor of trypsin (IC50 = 2.8 µM), and thus is the first described cyanobacterial serine protease inhibitor of an alkaloid structure. The function of nostocarboline in aquatic ecosystems and its potential as a lead compound for the development of useful therapeutic AChE inhibitors is discussed.

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References

  • Bartolini M, Bertucci C, Cavrini V, Andrisano V (2003) Beta-amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 65:407–416

    Article  PubMed  CAS  Google Scholar 

  • Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417

    Article  PubMed  CAS  Google Scholar 

  • Baumann HI, Keller S, Wolter FE, Nicholson GJ, Jung G, Süssmuth RD, Jüttner F (2007) Planktocyclin, a cyclooctapeptide protease inhibitor produced by the freshwater cyanobacterium Planktothrix rubescens. J Nat Prod 70:1611–1615

    Article  PubMed  CAS  Google Scholar 

  • Becher PG, Jüttner F (2005) Insecticidal compounds of the biofilm-forming cyanobacterium Fischerella sp. (ATCC 43239). Environ Toxicol 20:363–372

    Article  PubMed  CAS  Google Scholar 

  • Becher PG, Beuchat J, Gademann K, Jüttner F (2005) Nostocarboline: isolation and synthesis of a new cholinesterase inhibitor from Nostoc 78–12A. J Nat Prod 68:1793–1795

    Article  PubMed  CAS  Google Scholar 

  • Becher PG, Jüttner F (2006) Insecticidal activity—a new bioactive property of the cyanobacterium Fischerella. Pol J Ecol 54:653–662

    Google Scholar 

  • Becher PG, Keller S, Jung G, Süssmuth RD, Jüttner F (2007) Insecticidal activity of 12-epi-hapalindole J isonitrile. Phytochemistry 68:2493–2497

    Article  PubMed  CAS  Google Scholar 

  • Bisswanger H (2000) Enzymkinetik—Theorie und Methoden. Wiley-VCH, Weinheim

    Google Scholar 

  • Blom J, Bister B, Bischoff D, Nicholson G, Jung G, Süssmuth RD, Jüttner F (2003) Oscillapeptin J, a new grazer toxin of the freshwater cyanobacterium Planktothrix rubescens. J Nat Prod 66:431–434

    Article  PubMed  CAS  Google Scholar 

  • Blom JF, Brutsch T, Barbaras D, Bethuel Y, Locher HH, Hubschwerlen C, Gademann K (2006) Potent algicides based on the cyanobacterial alkaloid nostocarboline. Org Lett 8:737–740

    Article  PubMed  CAS  Google Scholar 

  • Burja AM, Banaigs B, Abou-Mansour E, Burgess JG, Wright PC (2001) Marine cyanobacteria—a prolific source of natural products. Tetrahedron 57:9347–9377

    Article  CAS  Google Scholar 

  • Carmichael WW (1992) Cyanobacteria secondary metabolites—the cyanotoxins. J Appl Bacteriol 72:445–459

    PubMed  CAS  Google Scholar 

  • Codd GA (1995) Cyanobacterial toxins: occurrence, properties and biological significance. Water Sci Technol 32:149–156

    Article  CAS  Google Scholar 

  • Dembitsky VM, Řezanka T (2005) Metabolites produced by nitrogen-fixing Nostoc species. Folia Microbiol 50:363–391

    Article  CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  PubMed  CAS  Google Scholar 

  • Fahrney DE, Gold AM (1963) Sulfonyl fluorides as inhibitors of esterases. I. Rates of reaction with acetylcholine esterase, α-chymotrypsin, and trypsin. J Am Chem Soc 85:997–1000

    Article  CAS  Google Scholar 

  • Gademann K (2007) Cyanobacterial natural products for the inhibition of biofilm formation and biofouling. Chimia 61:373–377

    Article  CAS  Google Scholar 

  • Gearhart DA, Neafsey EJ, Collins MA (2002) Phenylethanolamine N-methyltransferase has β-carboline 2N-methyltransferase activity: hypothetical relevance to Parkinson’s disease. Neurochem Internat 40:611–620

    Article  CAS  Google Scholar 

  • Ghosal S, Bhattacharya SK, Mehta R (1972) Naturally occurring and synthetic β-carbolines as cholinesterase inhibitors. J Pharm Sci 61:808–810

    Article  PubMed  CAS  Google Scholar 

  • Grau S, Baldi A, Bussani R, Tian X, Stefanescu R, Przybylski M, Richards P, Jones SA, Shridhar V, Clausen T, Ehrmann M (2005) Implications of the serine protease HtrA1 in amyloid precursor protein processing. Proc Nat Acad Sci USA 102:6021–6026

    Article  PubMed  CAS  Google Scholar 

  • Haider S, Naithani V, Viswanathan PN, Kakkar P (2003) Cyanobacterial toxins: a growing environmental concern. Chemosphere 52:1–21

    Article  PubMed  CAS  Google Scholar 

  • Harel M, Kryger G, Rosenberry TL, Mallender WD, Lewis T, Fletcher RJ, Guss JM, Silman I, Sussman JL (2000) Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors. Protein Sci 9:1063–1072

    Article  PubMed  CAS  Google Scholar 

  • Horowitz AR, Denholm I (2001) Impact of insecticides resistance mechanisms on management and strategies. In: Ishaaya I (ed) Biochemical sites of insecticide action and resistance. Springer, Berlin, pp 323–338

    Google Scholar 

  • Hostettmann K, Borloz A, Urbain A, Marston A (2006) Natural product inhibitors of acetylcholinesterase. Curr Org Chem 10:825–847

    Article  CAS  Google Scholar 

  • Houghton PJ, Ren Y, Howes M-J (2006) Acetylcholinesterase inhibitors from plants and fungi. Nat Prod Rep 23:181–199

    Article  PubMed  CAS  Google Scholar 

  • Inestrosa NC, Alvarez A, Pérez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J (1996) Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16:881–891

    Article  PubMed  CAS  Google Scholar 

  • Jüttner F, Wu JT (2000) Evidence of allelochemical activity in subtropical cyanobacterial biofilms of Taiwan. Arch Hydrobiol 147:505–517

    Google Scholar 

  • Jüttner F, Wessel HP (2003) Isolation of di(hydroxymethyl)dihydroxypyrrolidine from the cyanobacterial genus Cylindrospermum that effectively inhibits digestive glucosidases of aquatic insects and crustacean grazers. J Phycol 39:26–32

    Article  Google Scholar 

  • Kawabata SI, Miura T, Morita T, Kato H, Fujikawa K, Iwanaga S, Takada K, Kimura T, Sakakibara S (1988) Highly sensitive peptide-4-methylcoumaryl-7-amide substrates for blood-clotting proteases and trypsin. Eur J Biochem 172:17–25

    Article  PubMed  CAS  Google Scholar 

  • Kleinschmidt S, Ziegeler S, Bauer C (2005) Cholinesterase inhibitors. Importance in anaesthesia, intensive care medicine, emergency medicine and pain therapy. Anaesthesist 54:791–799

    Article  PubMed  CAS  Google Scholar 

  • Kraut D, Goff H, Pai RK, Hosea NA, Silman I, Sussman JL, Taylor P, Voet JG (2000) Inactivation studies of acetylcholinesterase with phenylmethylsulfonyl fluoride. Mol Pharmacol 57:1243–1248

    PubMed  CAS  Google Scholar 

  • Kuhn W, Muller T, Grosse H, Rommelspacher H (1996) Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients. J Neural Transm 103:1435–1440

    Article  PubMed  CAS  Google Scholar 

  • Liao D-I, Qian J, Chisholm DA, Jordan DB, Diner BA (2000) Crystal structures of the photosystem II D1 C-terminal processing protease. Nat Struct Biol 7:749–753

    Article  PubMed  CAS  Google Scholar 

  • Mahmood NA, Carmichael WW (1987) Anatoxin-a(s), an anticholinesterase from the cyanobacterium Anabaena flos-aquae NRC-525–17. Toxicon 25:1221–1227

    Article  PubMed  CAS  Google Scholar 

  • Matsubara K, Collins MA, Akane A, Ikebuchi J, Neafsey EJ, Kagawa M, Shiono H (1993) Potential bioactivated neurotoxicants, N-methylated β-carbolinium ions, are present in human brain. Brain Res 610:90–96

    Article  PubMed  CAS  Google Scholar 

  • Metcalf JS, Codd GA (2004) Cyanobacterial toxins in the water environment. A review of current knowledge. Foundation for Water Research, Marlow, UK

    Google Scholar 

  • Miota F, Siegfried BD, Scharf ME, Lydy MJ (2000) Atrazine induction of cytochrome P450 in Chironomus tentans larvae. Chemosphere 40:285–291

    Article  PubMed  CAS  Google Scholar 

  • Nair JS, Ramaswamy NK (2004) Chloroplast proteases. Biol Planta 48:321–326

    Article  CAS  Google Scholar 

  • Park H-J, Kim S-S, Seong Y-M, Kim K-H, Goo HG, Yoon EJ, Min, DS, Kang S, Rhim H (2006) β-Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. J Biol Chem 281:34277–34287

    Article  PubMed  CAS  Google Scholar 

  • Robinson ESJ, Anderson NJ, Crosby J, Nutt DJ, Hudson AL (2003) Endogenous β-carbolines as clonidine-displacing substances. Ann N Y Acad Sci 1009:157–166

    Article  PubMed  CAS  Google Scholar 

  • Schott Y, Decker M, Rommelspacher H, Lehmann J (2006) 6-Hydroxy- and 6-methoxy-β-carbolines as acetyl- and butyrylcholinesterase inhibitors. Bioorg Med Chem Lett 16:5840–5843

    Article  PubMed  CAS  Google Scholar 

  • Scott LJ, Goa KL (2000) Galantamine: a review of its use in Alzheimer’s disease. Drugs 60:1095–1122

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–31

    Article  PubMed  CAS  Google Scholar 

  • Sturm A, Hansen PD (1999) Altered cholinesterase and monooxygenase levels in Daphnia magna and Chironomus riparius exposed to environmental pollutants. Ecotoxicol Environ Saf 42:9–15

    Article  PubMed  CAS  Google Scholar 

  • Sussman JL, Silman I (1992) Acetylcholinesterase: structure and use as a model for specific cation-protein interactions. Curr Opin Struct Biol 2:721–729

    Article  CAS  Google Scholar 

  • Taylor P (1991) The cholinesterases. J Biol Chem 266:4025–4028

    PubMed  CAS  Google Scholar 

  • Teichert A, Schmidt J, Porzel A, Arnold N, Wessjohann L (2007) Brunneins A-C, β-carboline alkaloids from Cortinarius brunneus. J Nat Prod 70:1529–1531

    Article  PubMed  CAS  Google Scholar 

  • Todorova AK, Jüttner F, Linden A, Plüss T, Philipsborn WV (1995) Nostocyclamide: a new macrocyclic, thiazole-containing allelochemical from Nostoc sp. 31 (Cyanobacteria). J Org Chem 60:7891–7895

    Article  CAS  Google Scholar 

  • Trost JT, Chisholm DA, Jordan DB, Diner BA (1997) The D1 C-terminal processing protease processing of photosystem II from Scenedesmus obliquus. Protein purification and gene characterization in wild type and processing mutants. J Biol Chem 272:20348–20356

    Article  PubMed  CAS  Google Scholar 

  • Volk RB (2005) Screening of microalgal culture media for the presence of algicidal compounds and isolation and identification of two bioactive metabolites, excreted by the cyanobacteria Nostoc insulare and Nodularia harveyana. J Appl Phycol 17:339–347

    Article  CAS  Google Scholar 

  • Volk RB, Furkert FH (2006) Antialgal, antibacterial and antifungal activity of two metabolites produced and excreted by cyanobacteria during growth. Microbiol Res 161:180–186

    Article  PubMed  CAS  Google Scholar 

  • Volk RB (2007) Studies on culture age versus exometabolite production in batch cultures of the cyanobacterium Nostoc insulare. J Appl Phycol 19:491–495

    Article  CAS  Google Scholar 

  • Volk RB, Mundt S (2007) Cytotoxic and non-cytotoxic exometabolites of the cyanobacterium Nostoc insulare. J Appl Phycol 19:55–62

    Article  CAS  Google Scholar 

  • Welker M, von Döhren H (2006) Cyanobacterial peptides—Nature’s own combinatorial biosynthesis. FEMS Microbiol Rev 30:530–563

    Article  PubMed  CAS  Google Scholar 

  • Wylie CR, Paul VJ (1988) Feeding preferences of the surgeonfish Zebrasoma flavescens in relation to chemical defenses of tropical algae. Mar Ecol Prog Ser 45:23–32

    Article  CAS  Google Scholar 

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Acknowledgement

This work was supported by the National Science Foundation, Bern, and Hydrobiologie-Limnologie Stiftung, Zürich.

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  1. Paul G. Becher

    Present address: Chemical Ecology Group, Swedish University of Agricultural Sciences (SLU), Box 44, 23053, Alnarp, Sweden

Authors and Affiliations

  1. Limnological Station, Institute of Plant Biology, University of Zürich, Seestrasse 187, 8802, Kilchberg, Switzerland

    Paul G. Becher, Heike I. Baumann & Friedrich Jüttner

  2. Chemical Synthesis Laboratory, SB-ISIC-LSYNC, Swiss Federal Institute of Technology (EPFL), 1015, Lausanne, Switzerland

    Karl Gademann

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Correspondence to Paul G. Becher.

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Becher, P.G., Baumann, H.I., Gademann, K. et al. The cyanobacterial alkaloid nostocarboline: an inhibitor of acetylcholinesterase and trypsin. J Appl Phycol 21, 103–110 (2009). https://doi.org/10.1007/s10811-008-9335-3

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  • DOI: https://doi.org/10.1007/s10811-008-9335-3

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