Directed biosynthesis of phytotoxic alkaloids in the cyanobacterium Nostoc 78-12A.
Nostocarboline, a chlorinated and N-methylated carbolinium alkaloid, displays potent and selective inhibition of photoautotrophic organisms as well as the malaria parasite Plasmodium falciparum, while showing very low toxicity to bacterial and fungal pathogens, rat myoblasts and crustaceans. New derivatives of nostocarboline incorporating Br, F or methyl substituents have been obtained through precursor-directed biosynthesis in Nostoc 78-12A (identical to Nostoc sp. ATCC 43238) by feeding this cyanobacterium with differently substituted tryptophan derivatives or 6-Br-norharmane (eudistomin N). These experiments substantiate the biosynthetic hypothesis and validate the inherent flexibility of the corresponding enzymes for metabolic engineering. The new derivatives inhibit the growth of the toxic-bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 above 1 microM. The mode of action of nostocarboline was investigated by using chlorophyll-a fluorescence imaging, and it was demonstrated that a decrease in photosynthesis precedes cell death, thus establishing the phytotoxic properties of this alkaloid.
Portmann
Cyril
C
Chemical Synthesis Laboratory, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
Prestinari
Cora
C
Myers
Theresa
T
Scharte
Judith
J
Gademann
Karl
K
D000470:Alkaloids / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002243:Carbolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D046931:Microcystis / Q000187:drug effects; D015394:Molecular Structure; D046937:Nostoc / Q000737:chemistry / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D018515:Plant Leaves / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D014026:Nicotiana / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D014118:Toxins, Biological / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology
D000470:Alkaloids; D002243:Carbolines; D014118:Toxins, Biological; C507037:nostocarboline