Mikrosistin biyosentez yolaklarının düzenlenmesi ve genetik mekanizmalar
Oksijenik fotosentetik bakteriler grubunda yer alan, sucul ve karasal çevrede çok yaygın bir yaşam alanı bulunan siyanobakteriler Mavi-yeşil alg farklı morfolojik yapıya sahiptirler. Siyanobakteriler, bir kısmı oldukça etkili toksin olan ribozomal olmayan peptidler, poliketidler ve alkoloidleri içeren biyoaktif sekonder metabolit üretebilmektedirler. Toksik siyanobakterilerin yaygın bir şekilde bulunması insan ve hayvan sağlığı için risk oluşturmaktadır. Siyanobakterial toksinler veya siyanotoksinler insanlarda karaciğer kanseri, dermal kontakt irritasyonlar, gastroenterit gibi hastalıklara sebep olmaktadır. Siyanotoksinler nörotoksinler,hepatotoksinler, sitotoksinler ve dermatotoksinler olmak üzere dört ana sınıfa ayrılırlar. Fakat yapısal olarak birbirlerinden oldukça farklıdırlar. Geçtiğimiz on yıl içerisinde dört temel siyanotoksinin: mikrosistin, nodularin, saksitoksin ve silindrospermopsin biyosentez yolakları biyokimyasal ve genetik olarak tanımlanmıştır. Mikrosistinlerin, insan ve hayvan intoksikasyonlarını içeren birçok vakadan sorumlu olduğu gösterilmiştir. Bu derleme ile mikrosistinin biyosentez yolaklarını, kimyasal, genetik ve toksikolojik özelliklerin açıklanmaya çalışılmıştır
The regulation of microcystin biosynthesis pathways and genetic mechanisms
The cyanobacteria blue-green algae , as they are commonly named, comprise a diverse group of oxygenic photosynthetic bacteria that inhabit a wide range of aquatic and terrestrial environments, and display incredible morphological diversity. Cyanobacteria produce bioactive secondary metabolites, including alkaloids, polyketides and non-ribosomal peptides, some of which are potent toxins. The common occurrence of toxic cyanobacteria causes problems for health of animals and human. Cyanobacterial toxins or cyanotoxins are responsible diseases such as liver cancer, dermal contact irritations and gastroenteritis in humans. The cyanotoxins divide four major classes: the neurotoxins, hepatotoxins, cytotoxins, and dermatoxins. However, this toxins are quite variety. The biosynthesis pathways of the four major cyanotoxins: microcystin, saxitoxin, nodularin and cylindrospermopsin, have been interpreted as biochemical and genetical in the past decade. Microcystins have been implicated in several cases of animal and human intoxications. This review summarizes biosynthesis pathways of microcystin, chemistry, genetic and toxicology
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- 1. Bull AT, Ward AC, Goodfellow M. Search and
discovery strategies for biotechnology: the
paradigm shift. Microbiol Mol Biol Rev, 2000; 64(3):
573-606.
- 2. Pilotto L, Hobson P, Burch MD, Ranmuthugala G,
Attewell R, Weightman W. Acute skin irritant
effects of cyanobacteria (blue-green algae) in
healthy volunteers. Aust N Z J Public Health, 2004;
28(3): 220-4.
- 3. Botes D, Wessels P, Kruger H, Runnegar M, Santikarn
S, Smith R, Barna J, Williams D. Structural studies
on cyanoginosins-LR, -YR, -YA, and -YM, peptide
toxins from Microcystis aeruginosa. J Chem Soc,
1985; 1: 2747–2748.
- 4. Pearson L, Mihali T, Moffitt M, Kellmann R, Neilan
B. On the chemistry, toxicology and genetics of
the cyanobacterial toxins, microcystin, nodularin,
saxitoxin and cylindrospermopsin. Mar Drugs, 2010;
8(5):1650-80.
- 5. Moore RE, Chen JL, Moore BS, Patterson GML,
Carmichael WW. Biosynthesis of microcystin-LR.
Origin of carbons in the Adda and Masp units. J Am
Chem Soc, 1991; 113: 5083–4.
- 6. Welker M, Von Dohren H. Cyanobacterial peptides
nature's own combinatorial biosynthesis. FEMS
Microbiol Rev, 2006; 30: 530–63.
- 7. Ziegler K, Diener A, Herpin C, Richter R, Deutzmann
R, Lockau W. Molecular characterization of
cyanophycin synthetase, the enzyme catalyzing the
biosynthesis of the cyanobacterial reserve material
multi-L-arginyl-poly-L-aspartate (cyanophycin). Eur
J Biochem, 1998; 254: 154–9.
- 8. Jochimsen EM, Carmichael WW, An JS, Cardo DM,
Cookson ST, Holmes CE, Antunes MB, de Melo
Filho DA, Lyra TM, Barreto VS, Azevedo SM, Jarvis
WR. Liver failure and death after exposure to
microcystins at a hemodialysis center in Brazil. N
Engl J Med, 1998; 338: 873–8.
- 9. Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi
F, Cogliano V. Carcinogenicity of nitrate, nitrite,
and cyanobacterial peptide toxins. Lancet Oncol,
2006 ; 7(8): 628-9.
- 10. Azevedo SM, Carmichael WW, Jochimsen EM,
Rinehart KL, Lau S, Shaw GR, EagleshamGK.Human
intoxication by microcystins during renal dialysis
treatment in Caruaru-Brazil, Toxicol, 2002; 27:181-
182: 441-6.
- 11. Gürbüz F, Metcalf JS, Karahan AG, Codd GA. Analysis
of dissolved microcystins in surface water samples
from Kovada Lake, Turkey. Sci Total Environ, 2009;
15: 407(13): 4038-46.
- 12. DeVries SE, Galey FD, Namikoshi M, Woo JC.
Clinical and pathologic findings of blue-green algae
(Microcystis aeruginosa) intoxication in a dog. J
Vet Diagn Invest, 1993; 5(3): 403-8.
- 13. Puschner B, Galey FD, Johnson B, Dickie CW,
Vondy M, Francis T, Holstege DM. Blue-green algae
toxicosis in cattle. J Am Vet Med Assoc, 1998;
1;213(11): 1605-7.
- 14. 14. Frazier K, Colvin B, Styer E, Hullinger G, Garcia
R. Microcystin toxicosis in cattle due to overgrowth
of blue-green algae. Vet Hum Toxicol, 1998; 40(1):
23-4.
- 15. Fitzgerald SD, Poppenga RH. Toxicosis dueto
microcystin hepatotoxins in three Holstein heifers.
J Vet Diagn Invest, 1993; 5(4): 651-3.
- 16. Kerr LA, McCoy CP, Eaves D. Blue-green algae
toxicosis in five dairy cows. J Am Vet Med Assoc,
1987; 1:191(7): 829-30.
- 17. Short SB, Edwards WC. Blue-green algae toxicoses
in Oklahoma. Vet Hum Toxicol, 1990; 32(6):
558-60.
- 18. Galey FD, Beasley VR, Carmichael WW, Kleppe
G, Hooser SB, Haschek WM. Blue-green algae
(Microcystis aeruginosa) hepatotoxicosis in dairy
cows. Am J Vet Res, 1987; 48(9): 1415-20.
- 19. Dillenberg HO, Dehnel MK. Toxic waterbloom
in Saskatchewan, 1959. Can Med Assoc J, 1960;
83(22): 1151-4.
- 20. Senior VE. Algal poisoning in Saskatchewan. Can J
Comp Med Vet Sci, 1960; 24(1): 26-31.
- 21. Carbis CR, Mitchell GF, Anderson JW, McCauley
I. The effects of microcystins on the serum
biochemistry of carp, Cyprinus carpio L., when the
toxins are administered by gavage, immersion and
intraperitoneal routes. J Fish Diseas, 1996; 19(2):
151-9.
- 22. Li XY, Chung IK, Kim JI, Lee JA. Subchronic oral
toxicity of microcystin in common carp (Cyprinus
carpio L.) exposed to Microcystis under laboratory
conditions. Toxicon, 2004; 15: 44(8): 821-7.
- 23. Fischer WJ, Dietrich DR. Pathological and
biochemical characterization of microcystininduced hepatopancreas and kidney damage in
carp (Cyprinus carpio). Toxicol Appl Pharmacol,
2000; 164(1): 73-81.
- 24. Tencalla FG, Dietrich DR, Schlatter C, Toxicity of
Microcystis aeruginosa peptide toxin to yearling
rainbow trout (Oncorhynchus mykiss). Aquat
Toxicol, 1994; 30(3): 215-24.
- 25. Ibelings BW, Bruning K, de Jonge J, Wolfstein
K, Pires LM, Postma J, Burger T. Distribution of
microcystins in a lake foodweb: No evidence for
biomagnification. Microb Ecol, 2005; 49(4): 487-500.
- 26. Runnegar MT, Gerdes RG, Falconer IR. The uptake
of the cyanobacterial hepatotoxin microcystin by
isolated rat hepatocytes. Toxicon, 1991; 29: 43–51.
- 27. Runnegar M, Berndt N, Kaplowitz N. Microcystin
uptake and inhibition of protein phosphatases:
effects of chemoprotectants and self-inhibition
in relation to known hepatic transporters. Toxicol
Appl Pharmacol, 1995; 134: 264–72.
- 28. Dawson RM. The toxicology of microcystins.
Toxicon, 1998; 36: 953–62.
- 29. Eriksson JE, Toivola D, Meriluoto JA, Karaki H,
Han YG, Hartshorne D. Hepatocyte deformation
induced by cyanobacterial toxins reflects inhibition
of protein phosphatases. Biochem Biophys Res
Commun, 1990; 173: 1347–53.
- 30. Sahin A, Tencalla FG, Dietrich DR, Mez K, Naegeli H.
Enzymatic analysis of liver samples from rainbow
trout for diagnosis of blue-green algae-induced
toxicosis. Am J Vet Res, 1995; 56: 1110–5.
- 31. Krishnamurthy T, Carmichael WW, Sarver EW.
Toxic peptides from freshwater cyanobacteria
(blue-green algae). I. Isolation, purification and
characterization of peptides from Microcystis
aeruginosa and Anabaena flos-aquae. Toxicon,
1986; 24: 865–73.
- 32. Dittmann E, Börner T.Genetic contributions to the
risk assessment of microcystin in the environment.
Toxicol Appl Pharmacol, 2005; 203(3):192-200.
- 33. Yoshizawa S, Matsushima R, Watanabe MF, Harada
K, Ichihara A, Carmichael WW, Fujiki H. Inhibition
of protein phosphatases by microcystins and
nodularin associated with hepatotoxicity. J Cancer
Res Clin Oncol, 1990; 116: 609–14.
- 34. Nishiwaki S, Fujiki H, Suganuma M, NishiwakiMatsushima R, Sugimura T. Rapid purification
of protein phosphatase 2A from mouse brain by
microcystin-affinity chromatography. FEBS Lett,
1991; 279: 115–8.
- 35. Falconer IR. Tumor promotion and liver injury
caused by oral consumption of cyanobacteria.
Environ Toxicol Water Qual, 1991; 6: 177–84.
- 36. Nishiwaki-Matsushima R, Ohta T, Nishiwaki S,
Suganuma M, Kohyama K, Ishikawa T, Carmichael
WW, Fujiki H. Liver tumor promotion by the
cyanobacterial cyclic peptide toxin microcystinLR. J Cancer Res Clin Oncol, 1992; 118: 420–4.
- 37. Yu S. Primary prevention of hepatocellular
carcinoma. J Gastroenterol Hepatol, 1995; 10:
674–82.
- 38. Tanabe Y, Sano T, Kasai F, Watanabe MM.
Recombination, cryptic clades and neutral
molecular divergence of the microcystin synthetase
(mcy) genes of toxic cyanobacterium Microcystis
aeruginosa. BMC Evol Biol, 2009; 9:115.
- 39. Tillett D, Dittmann E, Erhard M, von Dohren H,
Borner T, Neilan BA. Structural organization of
microcystin biosynthesis in Microcystis aeruginosa
PCC7806: an integrated peptide-polyketide
synthetase system. Chem Biol, 2000; 7: 753–64.
- 40. Christiansen G, Fastner J, Erhard M, Borner
T, Dittmann E. Microcystin biosynthesis in
planktothrix: genes, evolution, and manipulation.
J Bacteriol, 2003; 185: 564–72.
- 41. Rouhiainen L, Vakkilainen T, Siemer BL, Buikema
W, Haselkorn R, Sivonen K. Genes coding for
hepatotoxic heptapeptides (microcystins) in the
cyanobacterium Anabaena strain 90. Appl Environ
Microbiol, 2004; 70: 686–92.
- 42. Hicks LM, Moffitt MC, Beer LL, Moore B, Kelleher
NL. Structural characterisation of in vitro and
in vivo intermediates on the loading module of
microcystin synthetase. ACS Chem Biol, 2006; 1:
93–102.
- 43. Nishizawa T, Asayama M, Shirai M. Cyclic
heptapeptide microcystin biosynthesis requires
the glutamate racemase gene. Microbiology, 2001;
147: 1235–41.
- 44. Sielaff H, Dittmann E, Tandeau De Marsac N,
Bouchier C, Von Dohren H, Borner T, Schwecke T.
The mcyF gene of the microcystin biosynthetic
gene cluster from Microcystis aeruginosa encodes
an aspartate racemase. Biochem J, 2003; 373:
909–16.
- 45. Pearson LA. Barrow KD, Neilan BA. Characterization
of the 2-hydroxy-acid dehydrogenase McyI,
encoded within the microcystin biosynthesis gene
cluster of Microcystis aeruginosa PCC7806. J Biol
Chem, 2007; 282: 4681–92.
- 46. Pearson LA, Hisbergues M, Borner T, Dittmann E,
Neilan BA. Inactivation of an ABC transporter gene,
mcyH, results in loss of microcystin production in
the cyanobacterium Microcystis aeruginosa PCC
7806. Appl Environ Microbiol, 2004; 70: 6370–8.
- 47. Shi L, Carmichael WW, Miller I. Immuno-gold
localization of hepatotoxins in cyanobacterial
cells. Arch Microbiol, 1995; 16: 7–15.
- 48. Young FM, Thomson C, Metcalf JS, Lucocq JM,
Codd GA. Immunogold localisation of microcystins
in cryosectioned cells of Microcystis. J Struct Biol,
2005; 151: 208–14.
- 49. Kaebernick M, Neilan BA, Borner T, Dittmann
E. Light and the transcriptional response of the
microcystin biosynthesis gene cluster. Appl Environ
Microbiol, 2000; 66: 3387–92.
- 50. Mikalsen B, Boison G, Skulberg OM, Fastner J,
Davies W, Gabrielsen TM, Rudi K, Jakobsen KS.
Natural variation in the microcystin synthetase
operon mcyABC and impact on microcystin
production in Microcystis strains. J Bacteriol,
2003; 185: 2774–85.
- 51. Tooming-Klunderud A, Mikalsen B, Kristensen T,
Jakobsen KS. The mosaic structure of the mcyABC
operon in Microcystis. Microbiology, 2008; 154:
1886–99.
- 52. Sivonen K. Effects of light, temperature, nitrate,
orthophosphate, and bacteria on growth of and
hepatotoxin production by Oscillatoria agardhii
strains. Appl Environ Microbiol, 1990; 56: 2658–66.
- 53. Lukac M, Aegerter R. Influence of trace metals
on growth and toxin production of Microcystis
aeruginosa. Toxicon, 1993; 31: 293–305.
- 54. Van der Westhuizen AJ, Eloff JN. Effect of
temperature and light on the toxicity and growth
of the blue-green alga Microcystis aeruginosa (UV006). Planta, 1985; 163: 55–9.
- 55. Song L, Sano T, Li R, Watanabe M, Liu Y, Kaya
K. Microcystin production of Microcystis viridis
(cyanobacteria) under different culture conditions.
Phycol Res, 1998; 42: 19.
- 56. Davis TW, Berry DL, Boyer GL, Gobler CJ. The
effects of temperature and nutrients on the growth
and dynamics of toxic and non-toxic strains of
Microcystis during cyanobacteria blooms. Harmful
Algae, 2009; 8 : 715–25.
- 57. Tonk L, Visser PM, Christiansen G, Dittmann E,
Snelder EO, Wiedner C, Mur LR, Huisman J. The
microcystin composition of the cyanobacterium
Planktothrix agardhii changes toward a more toxic
variant with increasing light intensity. Appl Environ
Microbiol, 2005; 71: 5177–81.
- 58. Sevilla E, Martin-Luna B, Vela L, Bes MT, Fillat
MF, Peleato ML. Iron availability affects mcyD
expression and microcystin-LR synthesis in
Microcystis aeruginosa PCC7806. Environ Microbiol,
2008; 10: 2476–83.
- 59. Kaebernick M, Dittmann E, Borner T, Neilan
BA. Multiple alternate transcripts direct the
biosynthesis of microcystin, a cyanobacterial
nonribosomal peptide. Appl Environ Microbiol,
2002; 68: 449–55.
- 60. Meissner K, Dittmann E, Borner T. Toxic and nontoxic strains of the cyanobacterium Microcystis
aeruginosa contain sequences homologous to
peptide synthetase genes. FEMS Microbiol Lett,
1996;135: 295–303.
- 61. Dittmann E, Meissner K, Borner T. Conserved
sequences of peptide synthetase genes in
the cyanobacterium Microcystis aeruginosa.
Phycologia, 1996; 35: 62–7.
- 62. Neilan BA, Dittmann E, Rouhiainen L, Bass RA,
Schaub V, Sivonen K, Borner T. Nonribosomal peptide
synthesis and toxigenicity of cyanobacteria. J
Bacteriol, 1999; 181: 4089–97.
- 63. Kurmayer R, Kutzenberger T. Application of realtime PCR for quantification of microcystin genotypes
in a population of the toxic cyanobacterium
Microcystis sp. Appl Environ Microbiol, 2003; 69:
6723–30.
- 64. Kurmayer R, Dittmann E, Fastner J, Chorus I.
Diversity of microcystin genes within a population
of the toxic cyanobacterium Microcystis spp. in
Lake Wannsee (Berlin, Germany). Microb Ecol,
2002; 43: 107–8.
- 65. Zhang Z, Zhang XX, Qin W, Xu L, Wang T, Cheng
S, Yang L. Effects of microcystin-LR exposure on
matrix metalloproteinase-2/-9 expressionand
cancer cell migration. Ecotoxicol Environ Saf,
2012; 77: 88-93.
- 66. Xu L, Qin W, Zhang H, Wang Y, Dou H, Yu D, Ding Y,
Yang L, Wang Y. Alterations in microRNA expression
linked to microcystin-LR-induced tumorigenicity
in human WRL-68 Cells. Mutat Res, 2012; 18:
743(1-2): 75-82.
- 67. Zhao S, Xie P, Li G, Jun C, Cai Y, Xiong Q, Zhao
Y.The proteomic study on cellular responses of
the testes of zebrafish (Danio rerio) exposed to
microcystin-RR. Proteomics, 2012; 12(2): 300-12.
- 68. Srivastava A, Choi GG, Ahn CY, Oh HM, Ravi AK,
Asthana RK. Dynamics of microcystin production
and quantification of potentially toxigenic
Microcystis sp. using real-time PCR. Water Res,
2012; 1: 46(3): 817-27.
- 69. Cantor GH, Beckonert O, Bollard ME, Keun HC,
Ebbels TM, Antti H, Wijsman JA, Bible RH, Breau
AP, Cockerell GL, Holmes E, Lindon JC, Nicholson
JK. Integrated histopathological and urinary
metabonomic investigation of the pathogenesis of
Microcystin-LR toxicosis. Vet Pathol, 2012; in press.