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      Production of the Neurotoxin BMAA by a Marine Cyanobacterium

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          Abstract

          Diverse species of cyanobacteria have recently been discovered to produce the neurotoxic non-protein amino acid β-methylamino- L-alanine (BMAA). In Guam, BMAA has been studied as a possible environmental toxin in the diets of indigenous Chamorro people known to have high levels of Amyotrophic Lateral Sclerosis/ Parkinsonism Dementia Complex (ALS/PDC). BMAA has been found to accumulate in brain tissues of patients with progressive neurodegenerative illness in North America. In Guam, BMAA was found to be produced by endosymbiotic cyanobacteria of the genus Nostoc which live in specialized cycad roots. We here report detection of BMAA in laboratory cultures of a free-living marine species of Nostoc. We successfully detected BMAA in this marine species of Nostoc with five different methods: HPLC-FD, UPLC-UV, Amino Acid Analyzer, LC/MS, and Triple Quadrupole LC/MS/MS. This consensus of five different analytical methods unequivocally demonstrates the presence of BMAA in this marine cyanobacterium. Since protein-associated BMAA can accumulate in increasing levels within food chains, it is possible that biomagnification of BMAA could occur in marine ecosystems similar to the biomagnification of BMAA in terrestrial ecosystems. Production of BMAA by marine cyanobacteria may represent another route of human exposure to BMAA. Since BMAA at low concentrations causes the death of motor neurons, low levels of BMAA exposure may trigger motor neuron disease in genetically vulnerable individuals.

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          Diverse taxa of cyanobacteria produce beta-N-methylamino-L-alanine, a neurotoxic amino acid.

          Cyanobacteria can generate molecules hazardous to human health, but production of the known cyanotoxins is taxonomically sporadic. For example, members of a few genera produce hepatotoxic microcystins, whereas production of hepatotoxic nodularins appears to be limited to a single genus. Production of known neurotoxins has also been considered phylogenetically unpredictable. We report here that a single neurotoxin, beta-N-methylamino-L-alanine, may be produced by all known groups of cyanobacteria, including cyanobacterial symbionts and free-living cyanobacteria. The ubiquity of cyanobacteria in terrestrial, as well as freshwater, brackish, and marine environments, suggests a potential for wide-spread human exposure.
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            Synthesis of a fluorescent derivatizing reagent, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate, and its application for the analysis of hydrolysate amino acids via high-performance liquid chromatography.

            A highly reactive amine derivatizing reagent, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate, has been synthesized. In a rapid, one-step procedure, the compound reacts with amino acids to form stable unsymmetric urea derivatives which are readily amenable to analysis by reversed phase HPLC. Studies on derivatization conditions demonstrate excellent derivative yield over the pH range 8.2-10.0. Maximal yields are observed with a molar reagent excess of approximately three or greater. The reaction is extremely tolerant of common buffer salts and detergents, with no discernible decrease in reaction yield with well-buffered samples. Selective fluorescence detection of the derivatives with excitation at 250 nm and emission at 395 nm allows for the direct injection of the reaction mixture with no significant interference from the only major fluorescent reagent by-product, 6-aminoquinoline. Separation of the derivatized amino acids has been optimized on a C18 column with complete resolution in less than 35 min. Excellent response linearity is demonstrated over the concentration range 2.5-200 microM for all hydrolysate amino acids. Detection limits range from 40 fmol for phenylalanine to 800 fmol for cystine. Good compositional data could be obtained from the analysis of derivatized protein hydrolysates containing as little as 30 ng of sample.
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              A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam.

              As root symbionts of cycad trees, cyanobacteria of the genus Nostoc produce beta-methylamino-l-alanine (BMAA), a neurotoxic nonprotein amino acid. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. However, because BMAA is polar and nonlipophilic, a mechanism for its biomagnification through increasing trophic levels has been unclear. We report that BMAA occurs not only as a free amino acid in the Guam ecosystem but also can be released from a bound form by acid hydrolysis. After first removing free amino acids from tissue samples of various trophic levels (cyanobacteria, root symbioses, cycad seeds, cycad flour, flying foxes eaten by the Chamorro people, and brain tissues of Chamorros who died from amyotrophic lateral sclerosis/Parkinsonism dementia complex), we then hydrolyzed the remaining fraction and found BMAA concentrations increased 10- to 240-fold. This bound form of BMAA may function as an endogenous neurotoxic reservoir, accumulating and being transported between trophic levels and subsequently being released during digestion and protein metabolism. Within brain tissues, the endogenous neurotoxic reservoir can slowly release free BMAA, thereby causing incipient and recurrent neurological damage over years or even decades, which may explain the observed long latency period for neurological disease onset among the Chamorro people. The presence of BMAA in brain tissues from Canadian patients who died of Alzheimer's disease suggests that exposure to cyanobacterial neurotoxins occurs outside of Guam.
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                Author and article information

                Journal
                Mar Drugs
                MD
                Marine Drugs
                Molecular Diversity Preservation International
                1660-3397
                December 2007
                6 December 2007
                : 5
                : 4
                : 180-196
                Affiliations
                [1 ] Institute for Ethnomedicine, Box 3464, Jackson Hole, Wyoming 83001, USA; E-mails: sbanack@ 123456fullerton.edu (Sandra Anne Banack); holly@ 123456ethnomedicine.org (Holly E. Johnson); ladianaus@ 123456hotmail.com (Ran Cheng)
                [2 ] Department of Biological Science, California State University, Fullerton, California 92834, USA
                Author notes
                * Author to whom correspondence should be addressed; E-mail: paul@ 123456ethnomedicine.org
                Article
                md504180
                10.3390/md504180
                2365698
                18463731
                8ce43e49-7dfd-40ae-9a4c-622d66e85d46
                © 2007 by MDPI
                History
                : 17 November 2007
                : 4 December 2007
                Categories
                Full Original Paper

                Pharmacology & Pharmaceutical medicine
                als/pdc,nostoc,biomagnification,lc/ms/ms,motor neuron disease

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