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Bioactive Compounds from Marine Microbes

Bioactive Compounds from Marine Microbes. Bioactive Compounds from Algae (Part 2) Cyanobacteria (“Blue-Green Algae”) Bioactive Compounds from (Other) Marine Bacteria Bioactive Compounds from Marine Fungi. Algae. Monera (“Prokaryotes”). Protista. Plantae. Fungi. Animalia. Algae.

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Bioactive Compounds from Marine Microbes

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  1. Bioactive Compounds from Marine Microbes Bioactive Compounds from Algae (Part 2) Cyanobacteria (“Blue-Green Algae”) Bioactive Compounds from (Other) Marine Bacteria Bioactive Compounds from Marine Fungi

  2. Algae Monera (“Prokaryotes”) Protista Plantae Fungi Animalia

  3. Algae Prokaryotic Kingdom Monera (Bacteria) Cyanobacteria (“Blue-Green Algae”) Eukaryotic Kingdom Protista Dinophyta (“Dinoflagellates”) Raphidophyta (“Raphidophytes”) Bacillariophyta (“Diatoms”) Chrysophyta (“Golden Algae”) Chlorophyta (“Green Algae”) Phaeophyta (“Brown Algae”) Rhodophyta (“Red Algae”) “Microalgae” “Macroalgae”

  4. “Harmful Algal Blooms” (HABs)

  5. Eukaryotic HAB Toxins Syndrome Source SpeciesTarget Domoic Acid “Amnesic Shellfish Pseudonitzschia spp. Glutamate Poisoning” (ASP) Receptors Saxitoxin “Paralytic Shellfish Alexandrium tamarense Inhibits Poisoning” (ASP) Sodium Channels Brevetoxin “Neurotoxic Shellfish Karenia brevis Activates Poisoning” (ASP) (and others) Sodium “Florida Red Tide” Channels Ciguatoxin (and others) “Ciguatera FishGambierdiscus toxicus Activates Poisoning” (CFP) Sodium Channels Pectenotoxin (and others) “Diarrhetic Shellfish Dinophysis spp. ? Poisoning” (CFP)

  6. Polyketides from Dinoflagellates “Polyether Ladders” e.g. PbTx-1 Macrolides Linear Polyethers e.g. PTX-1 e.g. Okadaic Acid

  7. Polyketide Synthases (PKSs) are Modular Enzymes Enoyl reductase (ER) NADPH NADP+ b-ketoacyl synthase (KS) Dehydrase (DH) b-ketoacyl reductase (KR) CO2 H2O

  8. Polyketide Synthase (PKS) Acyl Carrier Protein (ACP) Acyl Transferase (AT) Enoyl Reductase (ER) Dehydratase (DH) Ketosynthase (KS) Ketoreductase (KR) AT Organism PKSI PKSII Prorocentrum lima + + P. hoffmanianum + - Karenia brevis + - Symbiodinium sp. + - Amphidinium operculatum + - KS AT ACP PKSI Primers Snyder et al. (2003) Mar. Biotechnol., 5 (1):1-12.

  9. Prokaryotic Algae Cyanobacteria (“Blue-Green Algae”) Monera (“Prokaryotes”) Protista Plantae Fungi Animalia

  10. Cyanobacteria (“Blue-Green Algae”) Photosynthetic Bacteria Oldest Organisms on the Earth (Fossil Record - 3.5 Billions Years!) Marine, Freshwater and Terrestrial Symbiosis - e.g. Lichen Stromatolites

  11. Pigments and Algae PBs4 Chl a1bcdCar. 2Xanth.3PC5PE6 Cyanobacteria x x x Dinoflagellata x x x x Bacillariophyta x x x x Chrysophyta x x x x Chlorophyta x x x Phaeophyta x x x x Rhodophyta x x x x 1Chl = Chlorophyll; 2Car. = Carotenoids; 3Xanth. = Xanthophylls; 4PB = Phycobilins (Phycobiloproteins); 5PC = Phyocyanin; 6PE = Phycoerythrin

  12. Cyanobacteria as HABs

  13. Cyanobacteria as HABs First Scientific Report of Toxic Cyanobacteria: George Francis (1878) Nature Lake Alexandria, Murray River, Australia “thick scum like green oil paint, some two to six inches thick, and as thick and pasty as porridge” “Unwholesome” for cattle and other livestock that drink at the water Nodularia spumigens

  14. Cases of Acute Poisoning by Toxic Cyanobacteria in Drinking Water L. Alexandria, Australia Livestock Poisoning Nodularia spumigens 1931 Charleston, WV Acute Gastroenteritis Unknown (Ohio River) (9,000 cases/60,000 pop.) 1966 Harare, Zimbabwe Gastroenteritis (children) Microcystis aeruginosa 1975 Sewickley, PA Acute Gastroenteritis Schizothrix calcicola (62% of 8,000 pop.) 1983 Armidale, Australia Liver damage (elevated M. aeruginosa g-glutamyltransferase) 1983 Palm Island, Australia Hepatoenteritis C. raciborskii (139 children) (cylindrospermopsin) 1993 Itaparica Dam, Brazil Gastroenteritis Anabaena, Microcystis (88 deaths, children) 1996 Caruaru, Brazil Liver failure Aphan., Oscillatoria (63 deaths) (microcystins)

  15. Toxins from Cyanobacterial HABs Neurotoxins Hepatotoxins Dermatotoxins

  16. Neurotoxins from Cyanobacteria: Anatoxin-a 1950s-1960s Paul Gorham and Colleagues Cultured Anabaena flos-aquae Isolated “Very Fast Death Factor” Anatoxin-a

  17. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases Acetylcholine Receptor (AChR) Synapse Acetylcholine (in vesicles)

  18. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases + + + + + + + + - - - - - - ++ -- K+ Ca2+ Na+

  19. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases + + + + + + + + - - - - - - ++ -- K+ Ca2+ Na+

  20. Ca2+ SR Ca2+ PKC Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases Na+ + + + + + + + + - - - - - - ++ -- K+ Ca2+ Na+

  21. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases

  22. Ca2+ SR Ca2+ PKC Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases Na+ + + + + + + + + - - - - - - ++ -- K+ Ca2+ Na+

  23. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases Na+ + + + + + + + + - - - - - - ++ -- Acetylcholinesterase K+ Ca2+ Na+

  24. Ca2+ SR Ca2+ PKC Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases Anatoxin-a Na+ + + + + + + + + - - - - - - ++ -- K+ Ca2+ Na+

  25. Anatoxin-a Irreversibly Binds Acetylcholine Receptors and Inhibits Acetylcholinesterases

  26. Neurotoxins from Cyanobacteria: Anatoxin-a(s) Anatoxin-a(s)

  27. Anatoxin-a(s) Inhibits Cholinesterases LD50 = 20 µg/kg (in mice) vs. LD50 of Anatoxin-a = 200 µg/kg (in mice)

  28. Neurotoxins from Cyanobacteria: Saxitoxin R4: R1R2R3 H H H STX GTX5 H H OSO3- GTX2 C1 H OSO3- H GTX3 C2 OH H H NeoSTX GTX6 OH H OSO3- GTX1 C3 OH OSO3- H GTX4 C4 Saxitoxin (STX) and Other “PSP Toxins”

  29. = STX (or TTX) STX Binds and Blocks Voltage-Gated Sodium Channels

  30. Hepatotoxins from Cyanobacteria: Microcystins e.g. Microcystin-LR

  31. Microcystin Structural Diversity Over 70 Variants of MIcrocystins!

  32. Microcystin Diversity Microcystin-LR

  33. Hepatotoxins from Cyanobacteria: Nodularin Nodularin

  34. Microcystins (and Nodularin) Accumulate in Liver Approximately 50% of Microcystin in Liver ATP-Dependent Carrier-Mediated Transport

  35. Microcystins and Primary Liver Cancer (PLC) Nandong District, Jiangsu Province, China Pond/ditch vs. Well as Drinking Water Supply ~ 24-Fold Higher Rate of PLC with Pond/Ditch Water 100.13 cases per 100,000 (pond/ditch) 4.28 cases per 100,000 (well) Microcystin Levels: Pond/Ditch: 60% samples positive, avg. 160 pg/mL Well: None detected Calculated 0.19 pg/day Seasonal Intake (4 mo./yr.) Yu, 1989, Primary Live Cancer, pp. 30-37; Harada et al., 1996, China Nat. Toxins, 4: 277-83; Ueno et al., 1996, Carcinogenesis 17: 1317-21

  36. Microcystins (and Nodularins) are PP1/2a Ser/Thr Protein Phosphatase Inhibitors MacKintosh et al. (1990) FEBS Lett. 264: 187-92.

  37. Non-Ribosomal Peptides are Characteristic of Cyanobacterial Toxins Methyl-dehydro-Ala (Mdha) Iso-D-Glu Adda D-Ala Leu Arg Iso-MeAsp

  38. Non-Ribosomal Peptide Synthetases (NRPSs) are Modular Enzymes A = Adenylation Domain C = Condensation Domain T (PCP) = Thiolation (Peptidyl Carrier) Domain

  39. Mixed NRPS/PKS Pathway for Synthesis of Microcystins

  40. Dermatotoxins from Cyanobacteria: Lyngbya Toxins Lynbyatoxin Aplysiotoxin

  41. Dermatotoxins from Cyanobacteria: Lyngbya Toxins

  42. Drugs from Cyanobacteria: Curacin-A Curacin A Curacin A Binds Colchicine Site of Tubulin and Inhibits Tubulin-Polymerization

  43. Drugs from NON-MARINE Cyanobacteria: Cryptophycin Cryptophycin 52 (LY355703)

  44. Cryptophycin Inhibits Tubulin Polymerization

  45. Cryptophycin 52 in Clinical Trials (Phase II) Clinical Response of Women with Ovarian Cancer Treated with LY355703 (n=24) ResponseNo.% Complete Remission 0 0 Partial Remission 3 12.5 Stable Disease 7 29.2 Progressive Disease 14 58.3 D’Agostino et al. (2006) Intl. J. Gyn. Cancer 16: 71-76.

  46. Drugs from Cyanobacteria: Spirulina?

  47. Bioactive Compounds from Heterotrophic Marine Bacteria Monera (“Prokaryotes”) Protista Plantae Fungi Animalia

  48. Bacteria: Kingdom Monera Shape Cocci = Sphere-Shaped Bacilli = Rod-Shaped Spirilla = Spiral-Shaped “Growth Form” Staph = Bacteria in Clusters Strep = Bacteria in Chains

  49. Classification of the Bacteria (i.e. Kingdom Monera) Gram-Negative Gram-Positive

  50. Classification of the Bacteria (i.e. Kingdom Monera) Eubacteria Gram-Positive Bacteria w/ Cell-Walls Gram-Negative Bacteria w/ Cell-Walls Bacteria w/o Cell-Walls (Mycoplasma) Archaebacteria

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