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Neurotoksyny Syntetyzowane Przez Sinice

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Neurotoksyny Syntetyzowane Przez Sinice View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Jagiellonian Univeristy Repository Wiadomości Botaniczne 52(3/4): 43–53, 2008 Neurotoksyny syntetyzowane przez sinice Jan BIAŁCZYK, Zbigniew LECHOWSKI, Beata BOBER BIAŁCZYK J., LECHOWSKI Z., BOBER B. 2008. Neurotoxins synthesized by cyanobacteria. Wiadomości Botaniczne 52(3/4): 43–53. Cyanobacterial neurotoxins constitute one of the most toxic substances synthesized by living organisms. They are characterised by an unusually quick action that brings about the death of humans or animals within seconds or a few minutes of their consumption without the possi- bility of administering an antidote. The mechanism by which they act involves disturbance of the process of Na+ ions transportation in the neuromuscular systems. The neurotoxins contain nitrogen in their composition and are mostly alkaloids. They are synthesized by cyanobacteria living at all ecological niches. Certain species of free-living cyanobacteria (for example, Cy- lindrospermopsis raciborskii, Scytonema sp.) or those entering into symbiosis with plants (for example Nostoc sp.) produce β-methylaminoalanine. This non-protein amino acid may act as a ‘slow toxin’ inducing neurodegenerative diseases (amyotrophic lateral sclerosis, parkinsonism, dementia complex). The article discusses the classifi cation and chemical composition of cy- anobacterial neurotoxins, the mechanism of their action as well as the environmental threats that arise with the appearance of cyanobacterial blooms. KEY WORDS: cyanobacterial blooms, secondary metabolites, toxins Jan Białczyk, Zbigniew Lechowski, Beata Bober, Zakład Fizjologii i Biologii Rozwoju Roślin Uniwersytetu Jagiellońskiego, ul. Gronostajowa 7, 30-386 Kraków, e-mail: [email protected] WSTĘP z pól (Antoniou et al. 2005). Sinice syntetyzują i wydalają do środowiska metabolity wtórne Okresowo pojawiające się zakwity niektórych o różnej bioaktywności. Wiele z tych związków gatunków sinic, żyjących w słodkowodnych wykazuje toksyczne działanie i staje się przy- i zasolonych zbiornikach były obserwowane od czyną zatruć: ludzi, bydła, psów, ptaków oraz wielu lat. Autorem pierwszego w literaturze na- zwierząt żyjących w wodzie między innymi: ukowej doniesienia o ich występowaniu w przy- ryb, małży, ślimaków i stawonogów (Gorham rodzie był Francis (1878), a dotyczyło ono et al. 1964, Gugger et al. 2005, Dittmann, Wie- masowego pojawienia się Nodularia sp. u ujścia gand 2006). Toksyny sinicowe oddziałują na rzeki Murray River w Australii. Od tego czasu organizmy w wyniku: kontaktu ze skórą, picia częstotliwość pojawiania zakwitów sinicowych zanieczyszczonej wody lub konsumpcji orga- stale wzrasta, co jest wynikiem eutrofi zacji nizmów wodnych stanowiących różne ogniwa zbiorników wody powodowanej między innymi łańcucha trofi cznego. Do chwili obecnej ziden- przedostawaniem się do nich zwiększonych tyfi kowano około 40 rodzajów sinic, które syn- ilości odpadów komunalnych i przemysłowych, tetyzują związki o różnej budowie chemicznej, w tym detergentów oraz nawozów sztucznych wykazujące potencjalne działanie toksyczne. 44 J. Białczyk et al. Na podstawie efektów ich oddziaływania u krę- stwierdzone u przedstawicieli gatunków wszyst- gowców, związki te zostały sklasyfi kowane kich sekcji sinic, w tym także tych wchodzących jako: hepatotoksyny (mikrocystyna, nodula- w symbiozę z tkankami niektórych roślin. ryna), cytotoksyny (np. cylindrospermopsyna), W drodze syntezy chemicznej otrzymano neurotoksyny (np. anatoksyna, saksitoksyna) analogi prawie wszystkich neurotoksyn. Neuro- i dermatotoksyny wywołujące choroby i podraż- toksyny są również nieocenionym narzędziem nienia skóry (np. lipopolisacharydy, lyngbyatok- biochemicznym wykorzystywanym do badań syna). Niektóre gatunki sinic mogą produkować funkcji receptorów kanałów jonowych. Ponadto, kilka rodzajów toksyn równocześnie, wykazują- mają one zastosowanie w farmacji oraz jako cych odmienny mechanizm działania i wywo- środki owadobójcze. łujących choroby różnych organów człowieka W niniejszym artykule zostanie przedsta- i zwierząt. Wykazano, że występowanie wielu wiony przegląd neurotoksyn pochodzenia sini- groźnych chorób, między innymi nowotworów, cowego, ich budowa chemiczna, właściwości, było w niektórych regionach świata, np. w Chi- mechanizm działania, jak również zagrożenia nach i Australii, skorelowane z zawartością środowiskowe, pojawiające się wraz z wystą- toksyn sinicowych w wodzie pitnej i/lub ich pieniem zakwitu sinic o określonym składzie stężeniem w konsumowanych zwierzętach gatunkowym. wodnych. Z tych względów, zawartość toksyn powinna być monitorowana w zbiornikach wody NEUROTOKSYNY SINIC pitnej i rekreacyjnej. SŁODKOWODNYCH Przedstawiany obecnie artykuł obejmuje in- formacje skoncentrowane na opisie neurotoksyn Do grupy tych związków zalicza się: ana- pochodzenia sinicowego, związków należących toksynę-a, homoanatoksynę-a i anatoksynę-a(s). do jednych z najbardziej toksycznych substancji Anatoksyna-a (Ryc. 1, ANTX-a) jest niesyme- produkowanych przez żywe organizmy. Za- tryczną, dicykliczną, wtórną aminą posiadającą grożenia związane z ich działaniem dotyczą szkielet homotropanowy, który strukturalnie zaburzeń procesu transportu jonów w neurosys- zbliżony jest do alkaloidu kokainy. W tok- temach organizmów zwierzęcych. Zawierają one sycznych ilościach jest ona produkowana przy w swoim składzie azot i w większości należą masowym pojawianiu się następujących sinic: do alkaloidów (Gerwick et al. 2001). Budowa Aphanizomenon sp., Anabaena flos-aquae, chemiczna niektórych z nich została poznana A. circinalis, Cylindrospermum sp., Plankto- już w latach siedemdziesiątych XX wieku. Od- thrix sp. (dawniej Oscillatoria), Microcystis krywane są jednak stale nowe związki, często aeruginosa (Devlin et al. 1977, Sivonen et al. o niezwykle wysokim stopniu toksyczności. 1989, Edwards et al. 1992) i Phormidium fa- Neurotoksyny produkowane przez sinice słod- vosum (Gugger et al. 2005). Śmierć organizmu kowodne i morskie charakteryzują się niezwykle następuje w ciągu kilku minut po kontakcie lub szybkim działaniem, prowadząc do śmierci konsumpcji anatoksyny-a, dlatego często jest osobnika, często w czasie kilku sekund lub ona nazywana „bardzo szybkim czynnikiem minut, bez możliwości zastosowania ratującego śmierci” (Gorham et al. 1964). Anatoksyna-a życie antidotum. Występowanie neurotoksyn jest ekstremalnie silnym agonistą receptorów nie jest ograniczone jedynie do słodkowodnych nikotyno-acetylocholinowych (nACh). Wiąże i morskich środowisk. Wzrastająca liczba infor- się ona z neuronowymi receptorami nACh, co macji potwierdza fakt, że stwardnienie boczne prowadzi do aktywacji nerwowo-mięśniowych zanikowe-choroba Parkinsona-kompleks de- receptorów nACh (Costa et al. 1990, Wonnacott mencji (ALS-PD) mogą być powodowane przez et al. 1991, Wonnacott, Gallagher 2006). Pozo- konsumpcję β-metyloaminoalaniny (BMAA). ruje ona działanie naturalnego neurotransmitera, Synteza i akumulacja tego związku zostały jakim jest acetylocholina (ACh), prowadząc Neurotoksyny syntetyzowane przez sinice 45 Ryc. 1. Budowa chemiczna neurotoksyn sinicowych. ANTX-a – anatoksyna-a, homoANTX-a – homoanatoksyna-a, ANTX- a(s) – anatoksyna-a(s), BMAA – β-metyloaminoalanina, STX – saksitoksyna, LTX – lyngbyatoksyna, ATX A – antillatoksyna A, JTX (typ C) – jamaikamid (typ C), KTX – kalkitoksyna. Fig. 1. Chemical structure of cyanobacterial neurotoxins. ANTX-a – anatoxin-a, homoANTX-a – homoanatoxin-a, ANTX-a(s) – anatoxin-a(s), BMAA – β-methylaminoalanine, STX – saxitoxin, LTX – lyngbyatoxin, ATX A – antillatoxin A, JTX (type C) – jamaicamide (type C), KTX – kalkitoxin. do depolaryzacji błon komórek nerwowych przez Ach-esterazę. Te dwie właściwości ana- i mięśni. Anatoksyna-a wykazuje większe po- toksyny-a powodują ponadstymulację tkanek winowactwo do receptora nACh niż sama nerwowo−mięśniowych i peryferycznych mięśni ACh (Carmichael et al. 1979), przez co silnie szkieletowych. Staje się to przyczyną paraliżu i trwale wiąże się z tym receptorem. Odmiennie funkcji oddechowych, a objawami są drgawki, niż ACh, anatoksyna-a nie jest hydrolizowana konwulsje i śmierć, która jest następstwem 46 J. Białczyk et al. uduszenia się organizmu (Carmichael et al. syntetyzowana przez Anabaena flos-aquae 1979, Carmichael 1997, Holladay et al. 1997). i A. lammermanii (Mahmood, Carmichael 1986, W badaniach przeprowadzonych in vitro, w za- Onodera et al. 1997). Symptomy zatruć powo- leżności od organizmu, dawka letalna wahała się dowane przez anatoksynę-a(s) są podobne do od 20 do 200 nM/kg (Swanson et al. 1986). Ana- wywoływanych przez anatoksynę-a, a różni je toksyna-a wykazuje większą stereoselektywność dodatkowo stymulacja produkcji śliny u krę- niż inni agoniści receptorów nikotynowych. Jest gowców. (S) w nazwie pochodzi od angielskiego to wynikiem wiązania się silniej tej toksyny z re- słowa salivation wskazującego na ślinienie (Car- ceptorem poprzez trzy lub więcej miejsc inte- michael 1997). Jej struktura chemiczna, jak rakcji. W warunkach naturalnych neurotoksyna i mechanizm działania, są jednak całkowicie ta występuje w formie dwóch enancjomerów. odmienne od dwóch poprzednio opisywanych Enancjomer (+)−anatoksyny-a może być nawet toksyn. Anatoksyna-a(s) jest naturalnie występu- do 1000 razy bardziej biologicznie aktywny jącym fosforanem organicznym, który w swoim niż (−)−anatoksyna-a (Swanson et al. 1986, działaniu jest podobny do syntetycznie otrzymy- Macallan et al. 1988). Enancjomer (+)−anatok- wanych tego typu związków, stosowanych jako syny-a
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