Diverse taxa of cyanobacteria produce
?-N-methylamino-L-alanine, a neurotoxic amino acid
Paul Alan Cox*†, Sandra Anne Banack‡, Susan J. Murch*, Ulla Rasmussen§, Georgia Tien¶, Robert Richard Bidigare¶,
James S. Metcalf?, Louise F. Morrison?, Geoffrey A. Codd?, and Birgitta Bergman§
*Institute for Ethnomedicine, National Tropical Botanical Garden, Kalaheo, HI 96741;‡Institute for Ethnomedicine and Department of Biological Science,
California State University, Fullerton, CA 92834;§Department of Botany, Stockholm University, S-106 91 Stockholm, Sweden;¶Center for Marine Microbial
Ecology and Diversity, University of Hawaii at Manoa, Honolulu, HI 96822; and?Division of Environmental and Applied Biology, School of Life Sciences,
University of Dundee, Dundee DD1 4HN, United Kingdom
Communicated by William S. Bowers, University of Arizona, Tucson, AZ, February 24, 2005 (received for review December 3, 2004)
but production of the known cyanotoxins is taxonomically spo-
radic. For example, members of a few genera produce hepatotoxic
microcystins, whereas production of hepatotoxic nodularins ap-
pears to be limited to a single genus. Production of known
neurotoxins has also been considered phylogenetically unpredict-
able. We report here that a single neurotoxin, ?-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.
biomagnification ? neurotoxin ? symbiosis ? amyotrophic lateral
classification sections of cyanobacteria based on axenic strains
(1). For example, the hepatotoxic cyclic heptapeptide micro-
cystins are produced by members of the genera Microcystis,
Anabaena, Planktothrix, Hapalosiphon, Anabaenopsis, and Nos-
toc. In contrast, production of the cyclic pentapeptide nodularins
appears to be limited to Nodularia among the free-living cya-
nobacterial genera, with indications of nodularin production by
cyanobacterial symbionts in a sponge (2). Phylogenetic investi-
gations have indicated an early and widespread occurrence of
genes involved in nonribosomal peptide synthesis, including
microcystin synthesis. Sporadic distribution of microcystin syn-
thesis in extant cyanobacteria appears to have occurred because
of repeated losses of genes for microcystin biosynthesis in the
later-derived lineages of these organisms (3). This pattern ap-
pears to have arisen because of an early development of micro-
cystin production followed by repeated gene loss in cyanobac-
terial evolution. The consequences of cyanobacterial toxins on
human health, water-based industries, recreation, and wildlife
are of increasing concern as eutrophication and rising global
temperatures trigger increases in the geographical extent, pop-
ulation densities, and duration of cyanobacterial blooms in fresh,
brackish, and marine waters. Human poisonings from cyanobac-
terial blooms can be serious; 150 persons who drank cyanobac-
teria-contaminated water in Australia were hospitalized, and
?50 kidney dialysis patients at a Brazilian clinic who were
exposed to microcystins died (4–7).
?-N-methylamino-L-alanine (BMAA), a nonprotein amino
acid, was found to be produced (8) by cyanobacterial root
symbionts of the genus Nostoc (9). Originally discovered in cycad
seeds (10), BMAA was suggested as a possible cause of the
amyotrophic lateral sclerosis?parkinsonism–dementia complex
(ALS?PDC) that has an extremely high rate of incidence among
the Chamorro people of Guam compared with incidence rates of
ALS elsewhere (11, 12). Although BMAA as a putative cause of
ALS?PDC was initially disputed (13), this hypothesis has re-
yanotoxin production by cyanobacteria appears to be of
wide, but irregular, occurrence throughout the five principal
cently regained attention when it was discovered that BMAA is
in the brain tissues of Chamorros who died of ALS?PDC, but not
in patients who died of causes unrelated to neurodegenerative
disease (8, 16, 17).
BMAA accumulates in ascending trophic levels within the
Guam ecosystem. Axenic cultures of Nostoc (isolated from the
coralloid roots of the cycad tree Cycas micronesica) produce
BMAA at 0.3 ?g?g. BMAA occurs at 37 ?g?g within mildly
infected C. micronesica coralloid roots, and at 3,556 ?g?g in the
flying foxes that forage on the sarcotesta of C. micronesica seeds,
a roughly 100-fold increase for each trophic level (8, 15, 18).
Because flying foxes are a traditional delicacy (19) of the
indigenous Chamorro people, this 10,000-fold increase in
BMAA concentration from cyanobacteria to flying foxes sug-
gests that the Chamorros may unwittingly ingest high levels of
BMAA in their traditional diet. Flying foxes are not the only
BMAA source in the Chamorro diet: cycad seed flour, which
shows little free BMAA after washing, releases up to 169 ?g?g
BMAA on acid hydrolysis (16). Other protein-associated frac-
tions from each organism in the Guam food chain typically
exhibit a 100-fold BMAA increase over the amount of free
BMAA (16). Once ingested, BMAA can be bound by proteins
within the body, resulting in a slow release of free BMAA over
through enzymatic cleavage, that BMAA is incorporated within
the actual amino acid sequence of the protein would add weight
to this hypothesis. Such a mechanism may explain the observed
long latency period of ALS?PDC among the Chamorros (16).
We suggest that the Chamorro people of Guam may not be the
only human population exposed to this cyanobacteria-produced
‘‘slow toxin’’ (20).
BMAA was recently discovered in the brain tissues of nine
Canadian Alzheimer’s patients, but it was not detected in the
brain tissues of 14 other Canadians who died of causes unrelated
to neurodegeneration (8, 16, 17). Because cycads are not part of
the Canadian flora, we suggested that cyanobacteria might be
the ultimate source of the BMAA in the Canadian Alzheimer’s
patients (8). We also found BMAA in other cyanobacterial–
plant symbioses (Azolla filiculoides, 2 ?g?g; Gunnera kauaiensis,
4 ?g?g) (8). These new findings raised additional questions. Is
BMAA produced by other taxa of cyanobacteria? Is the bio-
magnification of cyanobacteria-produced BMAA unique to the
Guam ecosystem or can it occur elsewhere?
Because molecular phylogenies unite the cyanobacteria into a
single monophyletic group (21), we decided to examine BMAA
production in representative free-living and morphological gen-
Freely available online through the PNAS open access option.
†To whom correspondence should be addressed. E-mail: email@example.com.
© 2005 by The National Academy of Sciences of the USA
April 5, 2005 ?
vol. 102 ?
(1) as well as in cyanobacterial symbionts isolated from lichen
and a diversity of plant species. We analyzed cyanobacterial
cultures maintained at the University of Dundee in Scotland,
Stockholm University in Sweden, and the University of Hawaii
in the United States, as well as natural bloom samples, by using
a fluorescent derivatization of amino acids coupled with HPLC
to quantify free and protein-associated BMAA for each sample
(Fig. 2). We then confirmed selected BMAA peaks through
Materials and Methods
Samples of cyanobacterial cultures maintained at the Universities
of Stockholm, Hawaii, and Dundee were analyzed for BMAA
production. Some cultures had been isolated from symbioses with
species of the flowering plant Gunnera or from lichens, hornworts,
and liverworts; others came from marine, brackish, and freshwater
environments collected throughout the world. Lyophilized samples
0.1 M trichloroacetic acid and centrifuged at 15,800 ? g for 3 min
to precipitate proteins. Bound BMAA was released from the
protein pellets by hydrolysis (6 M HCl at 110°C for 24 h). Extracts
underwent ultrafiltration before derivatization with 6-aminoquin-
olyl-N-hydroxysuccinimidyl carbamate. BMAA was quantified by
using a validated HPLC separation. Free amino acids were sepa-
rated by reverse-phase separation on a gradient HPLC system
(Waters 717 Automated Injector and 1525 Binary Solvent Delivery
System) and Waters Nova-Pak C18 column at 37°C. Individual
140 mM sodium acetate, 5.6 mM triethylamine (pH 5.2), and 60%
or 52% acetonitrile (15). The identity of the BMAA peak was
confirmed by comparison with an authenticated standard (Sigma)
and was reverified by a modified gradient elution. The concentra-
tion of BMAA in samples was determined by fluorescence detec-
Trichodesmium thiebautii (section III). (Scale bar: 100 ?m.) (b) The unicellular Synechococcus PCC 6301 (section I). (Scale bar: 1 ?m.) (c) The filamentous Symploca
PCC 8002 (section III). (Scale bar: 10 ?m.) (d) The filamentous, nonbranching, and heterocystous (H) Nostoc PCC 7107 (section IV). (Scale bar: 10 ?m.) (e) The
filamentous, heterocystous (H) and branching (arrow) Fischerella PCC 7521 (section V). (Scale bar: 15 ?m.)
Cyanobacterial strains that produce BMAA representing different morphological sections. (a) The bloom-forming, filamentous, and colony-forming
by using fluorescence detection.
Cox et al.
April 5, 2005 ?
vol. 102 ?
no. 14 ?
tion (Waters 2487 Dual-Fluorescence Detector) with excitation at
250 nm and emission at 395 nm. Detection of the 6-aminoquinolyl-
N-hydroxysuccinimidyl carbamate-derivatized BMAA depended
on concentration and comparison of equal amounts of BMAA and
a norleucine internal standard, resulting in a mean response of
51.2%. The lower limits of detection and lower limits of quantifi-
cation were determined by a concentration gradient of an authen-
injection for all analyses. The lower limits of quantification was
of quantification or were reported as not detected (Tables 1 and 2).
The presence of BMAA in the samples as well as the identity
and purity of the BMAA peak in the HPLC separations was
confirmed by liquid chromatography-MS by using the same
HPLC system in-line with a Micromass ZQ?EMD1000 MS
(Waters) mass spectrometer, single quadrapole MS with an
atmospheric pressure ionization source by using the electrospray
Table 1. BMAA in cyanobacteria isolated from symbioses
Cyanobacteria Host SymbiontFree BMAA, ?g?gProtein BMAA, ?g?g
Nostoc PCC 9305
Nostoc PCC 73102
Nostoc PCC 7422
Nostoc PCC 9229
ND, not detected.
Table 2. BMAA in free-living cyanobacteria
Cyanobacterial species?strain Section*Habitat OriginFree BMAA, ?g?g Protein BMAA, ?g?g
Microcystis PCC 7806
Microcystis PCC 7820
Prochlorococcus marinus CCMP1377
Synechocystis PCC 6308
Synechococcus PCC 6301
Chroococcidiopsis indica GQ2-7
Chroococcidiopsis indica GT-3-26
Myxosarcina burmensis GB-9-4
Myxosarcina concinna GT-7-6
Planktothrix agardhii NIES 595
Plectonema PCC 73110
Symploca PCC 8002
Anabaena PCC 7120
Anabaena variabilis ATCC 29413
Cylindrospermopsis raciborskii CR3
Nodularia harveyana CCAP 1452?1
Nostoc PCC 6310
Nostoc PCC 7107
Nostoc sp. CMMED 01
Calothrix PCC 7103
Chlorogloeopsis PCC 6912
Fischerella PCC 7521
Scytonema PCC 7110
Yellowstone, hot spring
ND, not detected.
*Morphological groupings are as defined in ref.1. Section I, unicellular cyanobacteria that reproduce by binary fusion or budding; section II, unicellular
cyanobacteria that reproduce by multiple fission or by both multiple fission and binary fission; section III, filamentous, nonheterocystous cyanobacteria that
divide in more than one plane.
†Estimate of concentration based on ?1 mg dry weight of sample.
‡BMAA was not detected in all samples of this isolate.
www.pnas.org?cgi?doi?10.1073?pnas.0501526102Cox et al.
ionization interface all controlled by the same computer. Com-
pounds were separated on a reverse-phase column (Nova-Pak
C18, 4 Fm, 3.9 ? 300 mm, Waters) heated at 30°C with a linear
gradient elution of acetonitrile (10–60% over 25 min) in water.
Nitrogen gas was purified and supplied to the electrospray
was identified through selective ion monitoring in both positive
and negative ion modes with detection of the derivatized parent
molecule and two daughter ions. All BMAA ions were detected
with a dwell time of 1 sec and a cone voltage of 35 V.
lichen and host plants of broad taxonomic diversity indicated that
73% (8?11) of these strains produced BMAA (Table 1).
For free-living cyanobacteria, we found that BMAA is pro-
duced by members of all five cyanobacterial sections, as well as
in 95% (20?21) of the genera tested, and 97% (29?30) of the
strains we tested, representing a wide phylogenetic and ecolog-
ical diversity (Table 2). Because we found BMAA in an isolate
of bloom-forming Nodularia from the Baltic Sea (Table 2), we
have now begun testing samples from freshwater and marine
cyanobacterial blooms. Our preliminary results are intriguing.
For example, Trichodesmium sp. concentrated from two sepa-
rate frozen 500-ml samples of seawater from a Hawaiian marine
bloom, collected August 18, 2004, had 0.0079 ?g?g and 0.0071
?g?g BMAA wet weight, respectively. The supernatant from the
pelleted Trichodesmium in seawater had detectable BMAA;
however, it was below our lower limits of quantification.
abundant, and ancient organisms on planet Earth, our finding
that all five sections and 95% of all genera of cyanobacteria
tested produce the neurotoxin BMAA is of both ecological and
evolutionary significance. For example, Trichodesmium blooms
oceans (Fig. 3). They are observable by satellite from earth orbit
and reflect light frequencies that allow taxonomic determination
of the cyanobacterium (22). Our detection of BMAA in samples
of Baltic Sea and oceanic blooms suggest that significant quan-
tities of BMAA may be released into the world’s oceans.
Previous analysis of marine blooms of Trichodesmium thiebautii
and Trichodesmium erythraeum have revealed high neurotoxicity
to mice, but the low molecular weight neurotoxic entitity re-
mained a mystery because peptide toxins and anatoxin-a could
not be detected in the bloom extracts (23); if this work is
repeated, we suggest that an analysis of BMAA be conducted.
Similarly, the occurrence of BMAA in Prochlorococcus (Table
2), the most abundant oxyphototroph found in tropical and
subtropical waters, could indicate a significant input of neuro-
toxin at the lowest trophic level of such marine ecosystems (24).
Although we found 95% of cyanobacterial genera and 97% of
cyanobacterial strains in our samples to produce BMAA, it is
possible that given the right conditions, all cyanobacteria are
capable of producing BMAA. Our data (Table 2) show significant
variance in the range of BMAA content between genera and
species, and also within the ratio of free to protein-bound BMAA.
This variance suggests that BMAA production and storage is a
samples of a single Calothrix culture taken 3 months apart showed
no BMAA in one sample but quantifiable amounts in the second,
and a similar situation was found in Nodularia spumigena. This
finding is unlike the situation for other known cyanotoxins (neuro-
and hepatotoxins), which seem to be consistently produced by
on October 30, 1998.
Satellite photograph of a Trichodesmium bloom by using SeaWiFS imagery for spectral imaging at 443, 490, and 550 nm off the eastern coast of Florida
Cox et al.
April 5, 2005 ?
vol. 102 ?
no. 14 ?
among genera (2). Additionally, as our analysis shows that free-
living (terrestrial, as well as freshwater, brackish, and marine)
cyanobacteria produce BMAA, symbiosis is not a prerequisite for
cyanobacterial BMAA production; instead, BMAA production
appears to be a common trait within the entire cyanobacterial
The widespread occurrence of BMAA in our survey suggests
that production of this unusual nonprotein amino acid may be a
synapomorphy, a common conserved evolutionary feature that
unites the cyanobacteria as a group. Because cyanobacteria were
among the earliest biological entities to develop on Earth, with
Precambrian fossil records conservatively stretching to 1.5 bil-
lion years B.P. (25), BMAA is likely to have been produced long
before the evolution of organisms with neuronal systems. If so,
any selective value of BMAA for the cyanobacteria must have
been initially unrelated to its neurotoxicity. Because BMAA
likely alters the tertiary conformation of proteins, and because
incorporation of BMAA into cyanobacterial peptides may occur
as the result of nonribosomal peptide synthesis (26), it is possible
that the function of certain aspects of cyanobacterial biochem-
istry may depend on the presence of this nonprotein amino acid.
Our analysis greatly expands the potential distribution of
BMAA in nature as well as the total quantity of BMAA released
to the environment. Before 2003, BMAA was known to occur
only in cycads, limiting potential human exposure to tropical and
subtropical terrestrial environments where cycads grow and then
only to indigenous peoples who consume cycad products or
animals that feed on cycads. However, these new data demon-
strate that BMAA is produced by cyanobacteria from geograph-
ical regions and diverse environments throughout the world
(Table 2). Because cyanobacteria function as primary producers
in many food chains, it is likely that human populations far from
Guam may be exposed to this environmental neurotoxin. This
suggestion is partially corroborated by the discovery of BMAA
in brain tissues of Canadian Alzheimer’s patients (16, 17).
In Guam, human exposure to high quantities of BMAA results
from unique components of the traditional Chamorro diet
including cycad tortillas, flying foxes, and possibly other feral
animals (8). Here, we show that cyanobacterial symbionts of
other plants also contain BMAA. Symbioses between cyanobac-
teria and plants are taxonomically uncommon but can be of
ecological importance. For example, ungulates that graze on
cyanolichen genera such as Peltigera (9, 27, 28) may ingest
BMAA at certain seasons of the year (Table 1). The ubiquity of
cyanobacteria in diverse terrestrial and aquatic environments
suggests that ingestion of BMAA may occur through even less
cyanobacterial hosts, bioaccumulation in additional food chains,
or exposure to cyanobacteria-contaminated water supplies.
The recent hypothesis that BMAA accumulates in proteins,
which collectively function as an endogenous neurotoxic reservoir
within the human body, and then is slowly released through time as
these proteins are metabolized (16) suggests that possible health
consequences of chronic exposure to low doses of BMAA deserve
further investigation. It may now be prudent to monitor BMAA
concentrations in drinking waters contaminated by cyanobacterial
blooms. BMAA concentrations should also be monitored within
that either directly consume cyanobacteria or forage on plants or
prey that may have accumulated cyanobacteria-produced BMAA.
as those generated by iron-laden dust in the Atlantic and Pacific
Oceans (29–31), a broader analysis of the production and fate of
BMAA in marine ecosystems is also needed.
We thank M. K. Asay and H. Johnson at the Institute for Ethnomedicine
for technical support and R. Honegger of the University of Zurich for
useful discussions of cyanolichens. We thank the Acacia Foundation
(Larkspur, CA), B. and J. Lane, P. and H. Henry, and C. Childs for
laboratory equipment, and N. Kuring of the National Aeronautics and
Space Administration (Washington, DC) and A. Subaramaniam of the
LaMont Doherty Observatory (Columbia University, NY) for satellite
imagery. This work was funded by grants from the Harold K. L. Castle
Foundation (Kailua, HI) (to P.A.C.); the Swedish Research Council
(Stockholm) (to B.B.); the European Commission (Brussels) (to
G.A.C.); the Swedish International Development Cooperation Agency
(Stockholm) (to U.R.); National Institute for Environmental Health
Sciences (Research Triangle Park, NC) (to R.R.B.); and the National
Science Foundation (Arlington, VA) (to R.R.B.).
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Corrections Download full-text
BIOCHEMISTRY. For the article ‘‘Scanning the human proteome for
calmodulin-binding proteins,’’ by Xinchun Shen, C. Alexander
Valencia, Jack Szostak, Biao Dong, and Rihe Liu, which ap-
peared in issue 17, April 26, 2005, of Proc. Natl. Acad. Sci. USA
(102, 5969–5974; first published April 19, 2005; 10.1073?
pnas.0407928102), the author name Jack Szostak should have
appeared as Jack W. Szostak. The online version has been
corrected. The corrected author line appears below.
Xinchun Shen, C. Alexander Valencia, Jack W. Szostak,
Biao Dong, and Rihe Liu
The authors note several additions to the author contribution
footnote. The corrected author contribution footnote, which
appears online only, is shown below.
Author contributions: X.S., C.A.V., J.W.S., B.D., and R.L.
designed research; X.S., C.A.V., B.D., and R.L. performed
research; R.L. contributed new reagents?analytic tools; X.S.,
C.A.V., B.D., and R.L. analyzed data; and X.S., C.A.V., J.W.S.,
and R.L. wrote the paper.
ECOLOGY. For the article ‘‘Diverse taxa of cyanobacteria produce
?-N-methylamino-L-alanine, a neurotoxic amino acid,’’ by Paul
Alan Cox, Sandra Anne Banack, Susan J. Murch, Ulla Rasmus-
sen, Georgia Tien, Robert Richard Bidigare, James S. Metcalf,
Louise F. Morrison, Geoffrey A. Codd, and Birgitta Bergman,
USA (102, 5074–5078; first published April 4, 2005; 10.1073?
pnas.0501526102), the authors note that on page 5074, the first
sentence of the second full paragraph, right column, should read
‘‘BMAA was recently discovered in the brain tissues of eight of
nine Alzheimer’s patients,’’ and not ‘‘BMAA was recently
discovered in the brain tissues of nine Canadian Alzheimer’s
patients.’’ The authors also note on page 5075, first line in the
right column, ‘‘Lyophilized samples (5–20 ?g dry weight)’’
should read ‘‘Lyophilized samples (5–20 mg dry weight).’’ In
addition, on page 5076, the unit quantification ‘‘mol’’ in both
columns (line 8 in left column; line 1 in right column) should
read ‘‘?mol.’’ These errors do not change the conclusion of the
IMMUNOLOGY. For the article ‘‘Recombinant NY-ESO-1 protein
with ISCOMATRIX adjuvant induces broad integrated anti-
body and CD4? and CD8? T cell responses in humans,’’ by Ian
D. Davis, Weisan Chen, Heather Jackson, Phillip Parente, Mark
Shackleton, Wendie Hopkins, Qiyuan Chen, Nektaria Dimo-
poulos, Tina Luke, Roger Murphy, Andrew M. Scott, Eugene
Maraskovsky, Grant McArthur, Duncan MacGregor, Sue Stur-
rock, Tsin Yee Tai, Simon Green, Andrew Cuthbertson, Darryl
Maher, Lena Miloradovic, Susan V. Mitchell, Gerd Ritter,
Achim A. Jungbluth, Yao-Tseng Chen, Sacha Gnjatic, Eric W.
Hoffman, Lloyd J. Old, and Jonathan S. Cebon, which appeared
in issue 29, July 20, 2004, of Proc. Natl. Acad. Sci. USA (101,
10697–10702; first published July 13, 2004; 10.1073?
pnas.0403572101), the authors note that on page 10701, first
column, second full paragraph, ‘‘With a median followup of 748
days, 16 have relapsed: five of seven placebo pts, nine of 16 who
received protein alone and two of 19 who received NY-ESO-1
with IMX’’ should read: ‘‘With a median followup of 748 days,
16 have relapsed: five of seven placebo pts, six of 16 who received
The conclusions of the article remain unchanged.
PLANT BIOLOGY. For the article ‘‘The Arabidopsis SUMO E3 ligase
SIZ1 controls phosphate deficiency responses,’’ by Kenji Miura,
S. Karthikeyan, Kashchandra G. Raghothama, Dongwon Baek,
Yoon Duck Koo, Jing Bo Jin, Ray A. Bressan, Dae-Jin Yun, and
Paul M. Hasegawa, which appeared in issue 21, May 24, 2005, of
Proc. Natl. Acad. Sci. USA (102, 7760–7765; first published May
13, 2005; 10.1073?pnas.0500778102), the authors note that in the
Acknowledgments, the ‘‘Ministry of Science and Technology’’
was inadvertently identified as the ‘‘Ministry of Sports and
Technology,’’ due to a printer’s error.
July 5, 2005 ?
vol. 102 ?